1-Aryl-2-N-, S- or O-substituted benzimidazole derivatives, their use for the production of pharmaceutical agents as well as pharmaceutical preparations that contain these derivatives

ABSTRACT

The invention relates to novel benzimidazole derivatives with general formula I, whereby radicals R 1 , R 2 , R 3 , A, B, Y and Z have the meanings that are indicated in the description and the claims, the use of these compounds for the production of a pharmaceutical agent for treatment and prevention of diseases associated with microglia activation as well as pharmaceutical preparations that contain these compounds

This application claims the benefit of U.S. Provisional application No.60/304,124 filed Jul. 11, 2001.

The invention relates to new benzimidazole derivatives and the use ofbenzimidazole derivatives for the production of pharmaceutical agentsfor treatment and prevention of diseases that are associated with amicroglia activation as well as pharmaceutical preparations that containthe new benzimidazole derivatives.

Almost all degenerative diseases of the central nervous system areassociated with chronic inflammation. A central step of the inflammationprocess is the activation of mononuclear phagocyte cells, the microglia.This is carried out in, for example, Alzheimer's disease by senileplaques, in Creutzfeldt-Jacob disease by a prion protein and in ischemicstroke by dead cells. The microglia can remain for a prolonged period inthe activated state, in which they produce and secrete variousinflammation factors, for example, reactive oxygen/nitrogen intermediateproducts, proteases, cytokines, complement factors and neurotoxins. Thelatter in turn produce neuronal dysfunction and degeneration.

To treat inflammations and arteriosclerosis, i.a., benzimidazolederivatives had been proposed as active ingredients:

For example, in EP 0 104 727 A1, benzimidazole derivatives are indicatedthat are not substituted in 1-position and have an alkyl group in2-position. Substituents in the benzene ring of the derivatives are,i.a., pyridyloxy radicals, pyridylalkyl radicals, pyridylalkyloxyradicals and pyridyloxyalkanediyl radicals.

In WO 01/21634 A1, benzimidazole derivatives are also described that in1-position an alkanediylamido group can be substituted with at least onesubstituted alkoxy, alkylamino, alkylsulfonyl and alkylsulfoxideradical; in 2-position, i.a., a substituted phenyl or heteroaryl radicalcan be substituted with at least one substituted alkoxy, alkylamino,alkylsulfonyl and alkylsulfoxide radical; and on the anellated benzenering, i.a., with at least one substituted alkoxy, alkylamino,alkylsulfonyl and alkylsulfoxide radical. It is indicated that thesesubstances can be used for a considerable number of possible indicationsas active ingredients in pharmaceutical agent preparations.

In U.S. Pat. No. 5,552,426, substituted benzimidazoles are indicatedthat have in 1-position, i.a., a phenyl or naphthyl radical, and in2-position, i.a., a phenyl or heterocyclic radical. The anellatedbenzene ring of the benzimidazoles is preferably substituted with analkoxy or aminoalkoxy radical. An effectiveness against diseases isascribed to such compounds that are based on a neurotoxicity that isassociated with a β-amyloid-peptide.

In WO 97/12613 A1, various agents that have an anti-inflammatory actionand an arteriosclerosis-prophylactic action are described. For example,benzimidazole derivatives are indicated as active ingredients that aresubstituted in 1-position, i.a., with a phenyl radical or substitutedphenyl radical and in 2-position with an alkoxy radical. Substituents inthe benzene ring of the active ingredient compounds can be, i.a., alkyl,nitro, halo, alkoxy, amino, ester, amide, alkanediylalkoxy andalkanediylamino radicals.

In EP 0 520 200 A2, benzimidazole derivatives are indicated that havearyl radicals that are substituted in 1-position and amino groups thatare monosubstituted or disubstituted in the 2-position or areunsubstituted. The benzene ring of the benzimidazole skeleton can besubstituted with halogen, trifluoromethyl and/or cyano. These compoundsare used to treat diseases that are associated with an increasedactivation of Ca channels.

In WO 97/33873 A1, benzimidazole derivatives are also indicated that areused to treat cystitis. These compounds can have in 1-position, i.a.,phenyl, naphthyl and unsaturated heterocyclic radicals. In 2-position,the derivatives can be substituted with alkoxy, phenylalkoxy,naphthylalkoxy, heterocyclic alkoxy radicals or unsaturated heterocyclicalkoxy radicals. The benzene ring of the skeleton of the derivatives canbe substituted with nitro, alkanoyl, amino, alkyl, alkoxy, cycloalkyl,heterocyclic, unsaturated heterocyclic, halo, alkylthio,hydroxyalkylidenyl, hydroxyalkylidenylamino, aminoalkylidenyl,aminoalkoxy, hydroxyalkyl, heterocyclic alkoxy, aminoalkylidenyl ortrifluoromethyl radicals.

In EP 0 531 833 A1, condensed 5-membered heterocycles are indicated, forexample substituted benzimidazole derivatives, whereby these compoundsaccording to the general description of the compounds are preferablysubstituted in 1-position with a substituted alkyl radical and in2-position, for example, with an O-alkanediyl, S-alkanediyl,NH-alkanediyl, N(alkyl)-alkanediyl, SO-alkanediyl or SO₂-alkanediylradical. The anellated benzene ring can then be substituted, i.a., withan alkylenoxy, alkylenamino or alkylenamido group with a terminalcarboxyl group. Preferably included are those compounds that areunsubstituted in the 1-position or that carry an alkyl group. In thevery numerous examples, however, only compounds that carry an aryl orheterocyclic radical, especially a phenyl radical or an alkyl radical,in 1-position, are mentioned. The described compounds are to have anantithrombic action.

In the publications indicated above, it is only indicated that thedescribed active ingredients are suitable for treating thromboses,arteriosclerosis, cystitis and diseases that are associated with aβ-amyloid-peptide and with an increased activation of Ca-channels. Aneffect of the benzimidazole derivatives on microglia is not known fromthe documents, however.

For a possible treatment of neuroinflammation, to date non-steroidalanti-inflammatory agents (COX II inhibitors) [McGeer, P. L.; Roger,Neurology, 42, 447-449 (1992), Rogers, J.; Kirby, L. C.; Hempleman, S.R.; Berry, D. L.; McGeer, P. L.; Kaszniak, A. W.; Zalinski, J.; Cofield,M.; Mansukhani, L.; Wilson, P.; Kogan, F., Neurology, 43, 1609-1611(1993), Andersen, K.; Launer, L. J.; Ott, A.; Hoes, A. W.; Breteler, M.M. B.; Hofman, A., Neurology, 45, 1441-1445 (1995), Breitner, J. C. S.;Gau, B. A.; Welsh, K. A.; Plassman, B. L.; McDonald, W. M.; Helms, M.J.; Anthony, J. C., Neurology, 44, 227-232 (1994), The Canadian Study ofHealth and Aging, Neurology, 44, 2073-2079 (1994)], cytokine modulators[McGeer, P. L., McGeer, E. G. Brain Res. Rev., 21:195-218 (1995),McGeer, E. G.; McGeer, P. L., CNS Drugs, 7, 214-228 (1997), Barone, F.C. and Feuerstein, G. Z., J. Cerebral Blood Flow and Metabolism, 19,819-834 (1999)] and complement-cascade-inhibitors (Chen., S.;Frederickson, R. C. A., and Brunden, K. R., Neurobiol. Aging (1996),McGeer, E. G.; McGeer, P. L., Drugs, 55: 739-746 (1998)] have beendescribed.

This invention is based on the problem that the known substances inhibitthe synthesis or the action of individual inflammation factors without,however, the inflammation process being inhibited in an earlier step.The object therefore consists of finding substances that inhibit anearlier step in the inflammation process and thus prevent thedevelopment or the action of many inflammation factors.

The problem is solved by novel benzimidazole derivatives according toclaim 1, in addition by a use of the benzimidazole derivatives accordingto the invention for the production of pharmaceutical agents fortreatment of diseases that are associated with microglia activation andfor prevention of these diseases as well as pharmaceutical preparationsthat contain the benzimidazole derivatives according to the invention.

The benzimidazole derivatives according to the invention have thefollowing general structural formula I:

Here:

-   -   R¹ is an aryl group or a five- or six-membered heteroaryl group        with one or two heteroatoms, selected from the group that        comprises N, S and O, whereby the aryl group or heteroaryl group        can be substituted with up to three radicals, independently of        one another, selected from the group that comprises:        -   F, Cl, Br,        -   C(NH)NH₂, C(NH)NHR⁴, C(NH)NR⁴R^(4′), C(NR⁴)NH₂,            C(NR⁴)NHR^(4′),        -   C(NR⁴)NR⁴R^(4′),        -   X—OH, X—OR⁴, X—OCOR⁴, X—OCONHR⁴,        -   X—COR⁴, X—C(NOH)R⁴,        -   X—CN, X—COOH, X—COOR⁴, X—CONH₂, X—CONR⁴R^(4′), X—CONHR⁴,        -   X—CONHOH,        -   X—SR⁴, X—SOR⁴, X—SO₂R⁴,        -   SO₂NH₂, SO₂NHR⁴, SO₂NR⁴R^(4′),        -   NO₂, X—NH₂, X—NHR⁴, X—NR⁴R^(4′), X—NHSO₂R⁴, X—NR⁴SO₂R^(4′),        -   X—NHCOR⁴, X—NHCOOR⁴, X—NHCONHR⁴ and        -   R⁴,        -   whereby X is a bond, CH₂, (CH₂)₂ or CH(CH₃),        -   whereby also radicals R⁴ and R^(4′) are selected            independently of one another according to the meanings that            are further indicated below, and        -   whereby two substituents at R¹, if they are in            ortho-position to one another, are linked to one another in            such a way that they jointly form a methanediylbisoxy,            ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl            group,    -   Z is NH, NR^(2′), O, S, SO or SO₂, whereby R^(2′) has the        meaning that is indicated below,    -   R² and R^(2′), independently of one another, in each case are a        radical that is selected from the group that comprises:        -   C₁₋₄-perfluoroalkyl, C₁₋₆-alkyl, (C₀₋₃-alkanediyl-C₃₋₇            cycloalkyl), (C₀₋₃-alkanediyl-aryl) and            (C₀₋₃-alkanediyl-heteroaryl),        -   whereby the heteroaryl group is five- or six-membered and            contains one or two heteroatoms, selected from the group            that comprises N, S and O, and        -   whereby the aryl and heteroaryl group in each case can be            substituted with up to two radicals, selected from the group            that comprises F, Cl, Br, CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂,            CF₃, C₂F₅ and SO₂NH₂ and/or also can carry an anellated            methanediylbisoxy group or ethane-1,2-diylbisoxy group, and        -   in addition a ring member in a five-membered cycloalkyl ring            can be ring-N or ring-O, and one or two ring members in a            six- or seven-membered cycloalkyl ring can be ring-N and/or            ring-O atoms, whereby the ring-N atoms optionally can be            substituted with C₁₋₃-alkyl or C₁₋₃-alkanoyl,        -   or if Z is NR^(2′), R² and R^(2′) together with Z form a            five- to seven-membered heterocyclic ring, whereby the            heterocyclic ring also can contain another N, O or S atom,            and optionally can be substituted with a radical that is            selected from the group that comprises C₁₋₄-alkyl,            (C₀₋₃-alkanediyl-C₁₋₃-alkoxy), C₁₋₄-alkanoyl,            C₁₋₄-alkoxycarbonyl, aminocarbonyl and aryl,    -   R³ independently of one another, are one or two radicals,        selected from the group that comprises:        -   hydrogen,        -   F, Cl, Br,        -   OH, OR⁴, OCOR⁴, OCONHR⁴,        -   COR⁴,        -   CN, COOH, COOR⁴, CONH₂, CONHR⁴, CONR⁴R^(4′), CONHOH,        -   CONHOR⁴,        -   SR⁴, SOR⁴, SO₂R⁴, SO₂NH₂, SO₂NHR⁴, SO₂NR⁴R^(4′),        -   NO₂, NH₂, NHR⁴, NR⁴R^(4′),        -   NHSO₂R⁴, NR⁴SO₂R^(4′), NHSO₂R⁶, NR⁴SO₂R⁶,        -   NHCOR⁴, NHCOOR⁴, NHCONHR⁴ and R⁴,        -   whereby radicals R⁴, R^(4′) and R⁶ are selected            independently of one another according to the meanings that            are further indicated below,    -   A is a group that is selected from the group that comprises        C₁₋₁₀-alkanediyl, C₂₋₁₀-alkenediyl, C₂₋₁₀-alkinediyl and        (C₀₋₃-alkanediyl-C₃₋₇-cycloalkanediyl-C₀₋₃-alkanediyl),        -   whereby in a five-membered cycloalkyl ring, a ring member            can be ring-N or ring-O and in a six- or seven-membered            cycloalkyl ring, one or two ring members in each case can be            ring-N and/or ring-O atoms, whereby the ring-N atoms            optionally can be substituted with C₁₋₃-alkyl or            C₁₋₃-alkanoyl,        -   whereby in the above-mentioned aliphatic chains, a C atom            can be exchanged for O, NH, N—C₁₋₃-alkyl or N—C₁₋₃-alkanoyl            and whereby alkyl groups or cycloalkyl groups optionally can            be substituted with a radical that is selected from the            group that comprises ═O, OH, O—C₁₋₃ alkyl, NH₂,            NH—C₁₋₃-alkyl, NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂ and            N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl),    -   B is a radical that is selected from the group that comprises        COOH, COOR⁵, CONH₂, CONHNH₂, CONHR⁵, CONR⁵R^(5′), CONHOH,        CONHOR⁵ and tetrazolyl,        -   in each case bonded to a C atom of group A,        -   whereby radicals R⁵ and R^(5′), independently of one            another, are selected according to the meanings that are            further indicated below,    -   Y is a group that is selected from the group that comprises O,        NH, NR⁴, NCOR⁴, NSO₂R⁴ and NSO₂R⁶,        -   whereby R⁴ and R⁶ have the meanings that are further            indicated below,        -   in which in the above radicals, radicals R⁴, R^(4′), R⁵,            R^(5′) and R⁶ have the following meanings; here:    -   R⁴ and R^(4′), independently of one another, in each case are a        radical that is selected from the group that comprises CF₃,        C₂F₅, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₃-alkinyl and        (C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl),        -   whereby in a five-membered cycloalkyl ring, a ring member            can be ring-N or ring-O, and in a six- or seven-membered            cycloalkyl ring, one or two ring members can be ring-N            and/or ring-O atoms in each case, whereby the ring-N atoms            optionally can be substituted with C₁₋₃-alkyl or            C₁₋₃-alkanoyl,    -   R⁵ and R^(5′), independently of one another, in each case are a        radical that is selected from the group that comprises        C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl, whereby a C atom can be        exchanged for O, S, SO, SO₂, NH, N—C₁₋₃-alkyl or        N—C₁₋₃-alkanoyl, also (C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl),        -   whereby in a five-membered cycloalkyl ring, a ring member            can be ring-N or ring-O and in a six- or seven-membered            cycloalkyl ring, one or two ring members in each case can be            ring-N and/or ring-O atoms, whereby the ring-N atoms            optionally can be substituted with C₁₋₃-alkyl or            C₁₋₃-alkanoyl, and also (C₀₋₃-alkanediyl-aryl) and            (C₀₋₃-alkanediyl-heteroaryl), whereby the heteroaryl group            is five- or six-membered and contains one or two            heteroatoms, selected from the group that comprises N, S and            O,        -   whereby all previously mentioned alkyl and cycloalkyl            radicals with up to two radicals, selected from the group            that comprises CF₃, C₂F₅, OH, O—C₁₋₃ alkyl, NH₂, NH—C₁₋₃            alkyl, NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂,            N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl), COOH, CONH₂ and            COO—C₁₋₃-alkyl, and all previously mentioned aryl and            heteroaryl groups can be substituted with up to two            radicals, selected from the group that comprises F, Cl, Br,            CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂, N(CH₃)₂, CF₃, C₂F₅ and            SO₂NH₂ and/or can also carry an anellated methanediylbisoxy-            or ethane-1,2-diylbisoxy group,        -   or R⁵ and R^(5′) together with the amide-N atom of B form a            five- to seven-membered, saturated or unsaturated            heterocyclic ring, which can contain another N or O or S            atom, and which can be substituted with C₁₋₄-alkyl,            (C₀₋₂-alkanediyl-C₁₋₄-alkoxy), C₁₋₄-alkoxycarbonyl,            aminocarbonyl or aryl,    -   R⁶ is a radical that is selected from the group that comprises        (C₀₋₃-alkanediyl-aryl) and (C₀₋₃-alkanediyl-heteroaryl), whereby        the heteroaryl group is five- or six-membered and contains one        or two heteroatoms, selected from the group that comprises N, S        and O, and whereby the aryl and heteroaryl groups can be        substituted with up to two radicals, selected from the group        that comprises F, Cl, Br, CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂,        N(CH₃)₂, CF₃, C₂F₅, and SO₂NH₂ and/or can also carry an        anellated methanediylbisoxy group or ethane-1,2-diylbisoxy        group.

Preferred are those benzimidazole derivatives in which the substituentB-A-Y is bonded to the 6-position of the benzimidazole.

Preferred are also those benzimidazole derivatives in which Z has themeaning of NH, NR^(2′), S, SO or SO₂.

This invention also comprises physiologically compatible salts as wellas esters of the above-mentioned compounds, especially the acid salts ofthe nitrogen bases of the benzimidazole derivatives according to theinvention, also the salts of carboxylic acids of the derivativesaccording to the invention with bases, as well as the esters ofcarboxylic acids of the derivatives as well as carboxylic acids that arederived from carboxylic acid derivatives, for example carboxylic acidamides.

The benzimidazole derivatives according to the invention can have achiral center or several chiral centers, so that the compounds can occurin several isomeric forms. The compounds of formula I can also bepresent as tautomers, stereoisomers or geometric isomers. The inventionalso comprises all possible isomers, such as E- and Z-isomers, S- andR-enantiomers, diastereomers, racemates and mixtures of the sameincluding the tautomeric compounds. All of these isomeric compoundsare—unless expressly indicated otherwise in each case—components of thisinvention. The isomeric mixtures can be separated into enantiomers orE/Z-isomers according to commonly used methods, such as, for example,crystallization, chromatography or salt formation.

The heteroaryl groups that are contained in the benzimidazole compoundsaccording to the invention are built up from five or six skeleton atomsand can contain one or two heteroatoms. Heteroatoms are oxygen (O),nitrogen (N) and sulfur (S). Examples of heteroaryl groups are pyrrolyl,thienyl, firanyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl.If the heteroaryl groups are part of R¹ or R², the group is bonded via aC atom to the respective N atom of the benzimidazole skeleton or tosubstituent Z.

As aryl radicals, primarily the phenyl radicals, but also the naphthylradicals are suitable. The aryl and heteroaryl radicals can be bonded inany way to the benzimidazole skeleton or to another group, for exampleas a 1- or 2-naphthyl, 2-, 3- or 4-pyridinyl, 2-thienyl, 3-thienyl,3-furyl or 2-pyridiminyl.

Alkyl groups can be straight-chain or branched. Examples of alkyl groupsare methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl,n-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, n-hexyl, sec-hexyl,heptyl, octyl, nonyl, and decyl. The higher homologues also compriserespectively both the linear and the branched alkyl groups, thus, forexample, 2-ethylhexyl for octyl and 3-propyl-hexyl for nonyl.

Perfluorinated alkyls are preferably CF₃ and C₂F₅.

Alkenyl groups can be straight-chain or branched. For example, vinyl,2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 1-methyl-1-propenyl,2-methyl-2-propenyl and 3-methyl-2-propenyl are alkenyl radicals interms of the invention.

Alkinyl groups can be straight-chain or branched. Examples of this areethinyl, 1-propinyl, 2-propinyl, 1-butinyl and 2-butinyl.

Cycloalkyl groups are defined in each case preferably as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl (corresponds toC₃₋₇-cycloalkyl).

As a saturated heterocyclic ring or as cycloalkyl with one or moreheteroatoms, there can be mentioned, for example: piperidine,pyrrolidine, tetrahydrofuran, morpholine, piperazine, hexahydroazepineas well as 2,6-dimethyl-morpholine, N-phenyl-piperazine,methoxymethyl-pyrrolidine, whereby the linkage can be carried out with aC atom that is adjacent to the ring on optionally present ring-N atoms.

Alkanediyl, alkenediyl, alkinediyl and cycloalkanediyl radicals that arementioned in the description of the invention are the same in meaning asalkylene, alkenylene, alkinylene and cycloalkylene. If in the generalformulas of the alkanediyl radicals the number of the C atoms containedis indicated and the value 0 is indicated as a lower limit for the rangeof this number, this alkanediyl radical is not contained in therespective case.

As alkanes, alkenes and alkines for A, for example, the following arementioned: straight-chain or branched alkanediyl with one to eight Catoms, for example, methanediyl, ethanediyl, propanediyl, butanediyl,pentanediyl, hexanediyl, also 1-methylethanediyl, 1-ethylethanediyl,1-methylpropanediyl, 2-methylpropanediyl, 1-methylbutanediyl,2-methylbutanediyl, 1-ethylbutanediyl, 2-ethylbutanediyl,1-methylpentanediyl, 2-methylpentanediyl, 3-methylpentanediyl andanalogous compounds.

Straight-chain or branched alkenediyl and alkinediyl with two to eight Catoms are alkenediyl groups or alkinediyl groups with double and triplebonds in all possible positions and with all possible methyl or ethylsubstitutions. In these radicals, in each case one or two C atoms can beexchanged for O, NH, N—C₁₋₃-alkyl or N—C₁₋₃-alkanoyl, whereby theexchanged group is separated from Y by at least two C atoms.

If two radicals are in ortho-position, they can form a common ring withthe adjacent aromatic compounds. Compounds in which N, O or S atoms arebonded to olefinic or acetylenic multiple bonds, or in which several N,O, S or halogen atoms are bonded to the same aliphatic C atom, or inwhich N, O or S atoms are bonded to one another directly, are excludedif these linkages are not defined explicitly, for example in thefunctional groups or in heteroaromatic compounds that are mentioned inthe claim.

The physiologically compatible salts of the nitrogen bases of thebenzimidazole derivatives according to the invention can be formed withinorganic and organic acids, for example with oxalic acid, lactic acid,citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid,phosphoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid,p-toluenesulfonic acid, and methanesulfonic acid.

For salt formation of acid groups, especially carboxylic acid groups,inorganic or organic bases are also suitable that are known for theformation of physiologically compatible salts, such as, for example,alkali hydroxides, especially sodium and potassium hydroxide,alkaline-earth hydroxides, such as calcium hydroxide, also ammonia, aswell as amines, such as ethanolamine, diethanolamine, triethanolamine,N-methylglucamine and tris-(hydroxymethyl)-methylamine.

For ester formation, all lower monovalent, divalent and trivalentalcohols are suitable, especially methanol, ethanol, iso-propanol andtert-butanol, as well as ethylene glycol and glycerol.

Preferred are benzimidazoles with general formula I, in which theradicals and groups that are indicated below, independently of oneanother, have the following meanings:

-   -   R¹ means a phenyl group, which can be substituted with up to two        radicals, independently of one another, selected from the group        that comprises:        -   F, Cl, Br,        -   C(NH)NH₂, C(NH)NHR⁴, C(NH)NR⁴R^(4′), C(NR⁴)NH₂,            C(NR⁴)NHR^(4′),        -   C(NR⁴)NR⁴R^(4′),        -   OH, OR⁴, OCOR⁴, OCONHR⁴,        -   COR⁴, C(NOH)R⁴,        -   CN, COOH, COOR⁴, CONH₂, CONR⁴R^(4′), CONHR⁴,        -   CONHOH,        -   SR⁴, SOR⁴, SO₂R⁴,        -   SO₂NH₂, SO₂NHR⁴, SO²NR⁴R^(4′),        -   NO₂, NH₂, NHR⁴, NR⁴R^(4′), NHCONHR⁴ and        -   R⁴,        -   whereby radicals R⁴ and R^(4′) are selected independently of            one another according to meanings that are indicated below            and whereby two substituents at R¹ are linked to one another            in such a way that they jointly form a methanediylbisoxy,            ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl            group, if they are in ortho-position to one another,    -   Z has the same meaning as indicated above,    -   R² and R^(2′) have the same meanings as indicated above,    -   R³ means a radical that is selected from the group that        comprises hydrogen, F, Cl, Br, CH₃, C₂H₅, CF₃, C₂F₅, OH, OR⁴,        NHSO₂R⁶ and NHCOR⁴, whereby R⁴ and R⁶ have the meanings that are        further indicated below,    -   A has the same meaning as indicated above,    -   B means a radical that is selected from the group that comprises        COOH, COOR⁵, CONH₂, CONHR⁵ and CONR⁵R^(5′), in each case bonded        to a C atom of group A, whereby radicals R⁵ and R^(5′) are        selected independently of one another according to the meanings        that are further indicated above,    -   Y means O,        -   in which in the above radicals, radicals R⁴, R^(4′), R⁵,            R^(5′) and R⁶ have the following meanings; here:    -   R⁴ and R^(4′) have the same meanings as indicated above,    -   R⁵ and R^(5′), independently of one another, in each case mean a        radical that is selected from the group that comprises        C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl, whereby a C atom can be        exchanged for O, S, SO, SO₂, NH, N—C₁₋₃-alkyl or        N—C₁₋₃-alkanoyl, also (C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl), whereby        in a five-membered cycloalkyl ring, a ring member can be ring-N        or ring-O and in a six- or seven-membered cycloalkyl ring, one        or two ring members in each case can be ring-N atoms and/or        ring-O atoms, whereby the ring-N atoms optionally can be        substituted with C₁₋₃-alkyl or C₁₋₃-alkanoyl, and also        (C₀₋₃-alkanediyl-phenyl) and (C₀₋₃-alkanediyl-heteroaryl),        whereby the heteroaryl group is five- or six-membered and        contains one or two heteroatoms, selected from the group that        comprises N, S and O,        -   whereby all previously mentioned alkyl and cycloalkyl            radicals can be substituted with a radical that is selected            from the group that comprises CF₃, C₂F₅, OH, O—C₁₋₃ alkyl,            NH₂, NH—C₁₋₃-alkyl, NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂,            N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl), COOH, CONH₂ and COO—C₁₋₃            alkyl, and all previously mentioned phenyl and heteroaryl            groups can be substituted with up to two radicals, selected            from the group that comprises F, Cl, Br, CH₃, C₂H₅, OH,            OCH₃, OC₂H₅, NO₂, N(CH₃)₂, CF₃, C₂F₅ and SO₂NH₂, and/or also            can carry an anellated methanediylbisoxy group or            ethane-1,2-diylbisoxy group,        -   or R⁵ and R^(5′) together with the amide-N atom of B form a            five- to seven-membered, saturated or unsaturated            heterocyclic ring, which can contain another N or O or S            atom and which can be substituted with C₁₋₄-alkyl,            (C₀₋₂-alkanediyl-C₁₋₄-alkoxy), C₁₋₄-alkoxycarbonyl,            aminocarbonyl or phenyl,    -   R⁶ means a phenyl or heteroaryl group, whereby the heteroaryl        group is five- or six-membered and contains one or two        heteroatoms, selected from the group that comprises N, S and O,        and whereby the phenyl and heteroaryl groups can be substituted        with up to two radicals, selected from the group that comprises        F, Cl, Br, CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂, N(CH₃)₂, CF₃, C₂F₅        and SO₂NH₂, or else can carry an anellated methanediylbisoxy        group or ethane-1,2-diylbisoxy group.

Especially preferred are benzimidazoles with general formula I, in whichthe radicals and groups that are indicated below, independently of oneanother, have the following meanings:

-   -   R¹ means a phenyl group, which can be substituted with up to two        radicals, independently of one another, selected from the group        that comprises:        -   F, Cl, Br,        -   C(NH)NH₂, C(NH)NHR⁴, C(NH)NR⁴R^(4′), C(NR⁴)NH₂,            C(NR⁴)NHR^(4′),        -   C(NR⁴)NR⁴R^(4′),        -   OH, OR⁴, OCOR⁴, OCONHR⁴,        -   COR⁴, C(NOH)R⁴,        -   CN, COOH, COOR⁴, CONH₂, CONR⁴R^(4′), CONHR⁴,        -   CONHOH,        -   SR⁴, SOR⁴, SO₂R⁴,        -   SO₂NH₂, SO₂NHR⁴, SO²NR⁴R^(4′),        -   NO₂, NH₂, NHR⁴, NR⁴R^(4′), NHCONHR⁴ and        -   R⁴,        -   whereby radicals R⁴ and R^(4′) are selected independently of            one another according to meanings that are indicated below            and whereby two substituents at R¹ are linked to one another            in such a way that they jointly form a methanediylbisoxy,            ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl            group, if they are in ortho-position to one another,    -   Z has the same meaning as indicated above,    -   R² and R^(2′), independently of one another, in each case mean a        radical that is selected from        -   the group that comprises:        -   C₁₋₄-perfluoroalkyl, C₁₋₅-alkyl, (C₀₋₃-alkanediyl-aryl) and            (C₀₋₃-alkanediyl-heteroaryl),        -   whereby the heteroaryl group is five- or six-membered and            contains one or two heteroatoms, selected from the group            that comprises N, S and O, and        -   whereby the aryl and heteroaryl group in each case can be            substituted with up to two radicals, selected from the group            that comprises F, Cl, Br, CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂,            CF₃, C₂F₅ and SO₂NH₂,        -   or if Z is NR^(2′), R² and R^(2′) together with Z form a            five- to seven-membered heterocyclic ring, whereby also the            heterocyclic ring can contain an additional O or S atom and            optionally can be substituted with a radical that is            selected from the group that comprises C₁₋₄-alkyl,            (C₀₋₃-alkanediyl-C₁₋₃-alkoxy), C₁₋₄-alkanoyl,            C₁₋₄-alkoxycarbonyl, aminocarbonyl and aryl,    -   R³ means hydrogen,    -   A means straight-chain or branched alkanediyl with up to 8 C        atoms,    -   B means a radical that is selected from the group that comprises        COOH, COOR⁵, CONH₂, CONHR⁵ and CONR⁵R^(5′), in each case bonded        to a C atom of group A,        -   whereby radicals R⁵ and R^(5′) are selected independently of            one another according to the meanings that are further            indicated below,    -   Y means O,        -   in which in the above radicals, radicals R⁴, R^(4′), R⁵, and            R^(5′) have the following meanings; here:    -   R⁴ and R^(4′), independently of one another, in each case mean a        radical that is selected from        -   the group that comprises CF₃, C₂F₅, C₁₋₄-alkyl,            C₂₋₄-alkenyl, C₂₋₃-alkinyl and            (C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl),        -   whereby alkyl radicals optionally can be substituted with a            radical that is selected from the group that comprises OH,            OCH₃ and SCH₃,    -   R⁵ and R^(5′), independently of one another, in each case mean a        radical that is selected from the group that comprises        C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl,        (C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl), (C₀₋₃-alkanediyl-phenyl) and        (C₀₋₃-alkanediyl-heteroaryl), whereby the heteroaryl group is        five- or six-membered and contains one or two heteroatoms,        selected from the group that comprises N, S and O,        -   whereby all previously mentioned alkyl and cycloalkyl            radicals can be substituted with a radical that is selected            from the group that comprises CF₃, C₂F₅, OH, O—C₁₋₃-alkyl,            NH₂, NH—C₁₋₃-alkyl, NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂,            N(C₁₋₁₃-alkyl)(C₁₋₃-alkanoyl), COOH, CONH₂ and            COO—C₁₋₃-alkyl, and all previously mentioned phenyl and            heteroaryl groups can be substituted with up to two            radicals, selected from the group that comprises F, Cl, Br,            CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂, N(CH₃)₂, CF₃, C₂F₅ and            SO₂NH₂, and/or also can carry an anellated methanediylbisoxy            group or ethane-1,2-diylbisoxy group,        -   or R⁵ and R^(5′) together with the amide-N atom of B form a            five- to seven-membered, saturated or unsaturated            heterocyclic ring, which can contain another N or O or S            atom and which can be substituted with C₁₋₄-alkyl,            (C₀₋₂-alkanediyl-C₁₋₄-alkoxy), C₁₋₄-alkoxycarbonyl,            aminocarbonyl or phenyl.    -   R¹ is especially phenyl or methylphenyl. R² can preferably be a        radical that is selected from the group that comprises        C₁₋₃-alkyl, phenyl, methylphenyl, methanediylphenyl and        heteroaryl.        Z, together with R², can also form a saturated, 5- or 6-membered        heterocyclic ring that can contain an additional O or S atom,        such as, for example, a piperidine or morpholine ring.    -   R³ is preferably hydrogen. The grouping Y-A is set forth in a        preferred embodiment by an n-pentanedioxy group (—C₅H₁₀—O),        which is bonded via the O atom to the benzimidazole skeleton. As        an alternative, the groupings can also be used with shorter or        longer alkanediyl radicals, for example n-butanediyloxy or        n-hexanediyloxy.

Terminal group B preferably stands for COOH, COOR, whereby R inparticular can be C₁₋₄-alkyl, such as methyl, ethyl, iso-propyl ortert-butyl, or an amide group, for example, a C₁₋₆-alkylamido group,whereby alkyl in particular can be iso-propyl or iso-butyl, adialkylamido group, whereby alkyl in particular can be methyl, or a3-alkoxy-propanediyl-amino group, whereby alkoxy can be a methyloxy,iso-butyloxy or iso-pentyloxy group.

The structural features that are different from the individualderivatives are set forth in Table 2, whereby the indicated structuralfeatures relate to general formula II that is also indicated in theTable.

The benzimidazole derivatives according to the invention inhibit theactivation of microglia. Microglia are defined here as the macrophagesof the brain. The invention therefore also relates to the use of thesederivatives for the production of pharmaceutical agents for treatingdiseases that are associated with a microglia activation as well as forpreventing the diseases. In this case, a corresponding use of suchderivatives is also included with general formula I, in which B standsfor hydrogen, and in which radicals R¹, R², R³, A, B, Y and Z have theabove-indicated meanings. Other radicals R⁴, R⁵ and R⁶ that also definethese radicals or groups are also defined by the meanings that arefurther indicated above. In addition to the use of the new benzimidazolederivatives according to the invention for the production of theabove-mentioned pharmaceutical agents, the invention also relates to acorresponding use of benzimidazole derivatives, in which B stands forhydrogen. The use of these derivatives, which are used as components forpharmaceutical agents for treating diseases that are associated with amicroglia activation as well as for preventing these diseases, is new,even if these other compounds are not new themselves (U.S. Pat. No.5,552,426).

The compounds of formula I inhibit the activation of the microglia andthe production of interleukin 12 (IL 12) and interferon γ (INFγ). Theinvention therefore also relates to the use of a compound of formula I,as well as optical or geometric isomers thereof or tautomers orphysiologically compatible salts thereof for the production of apharmaceutical agent for treating or preventing a disease that isassociated with a microglia activation as well as a disease that istriggered by over-production of IL 12 and IFNγ and for induction ofinterleukin 10 (IL-10).

Based on their ability to inhibit the activation of microglia and tointerrupt the production of IL 12 and TNFα in monocytes/macrophages andthe INFγ production in T cells and NK cells and to increase theinduction of the IL-10 production, the compounds according to theinvention are suitable for treating numerous diseases that are triggeredby the intensified production of cytokines, such as, e.g., TNFα,β, IFNγ,IL 2 and IL12, such as inflammatory diseases, autoimmune diseases,allergic and infectious diseases, toxin-induced inflammations,pharmacologically triggered inflammation reactions as well aspathophysiologically relevant inflammation reactions of an origin thatis as yet unclear.

Examples of inflammatory and autoimmune diseases are: chronicinflammatory intestinal diseases (inflammatory bowel diseases, Crohn'sdisease, ulcerative colitis), arthritis, allergic contact dermatitis,psoriasis, pemphigus, asthma, multiple sclerosis, diabetes, type Iinsulin-dependent diabetes mellitus, rheumatoid arthritis, lupusdiseases and other collagenoses, Graves' disease, Hashimoto's disease,“graft-versus-host disease” and transplant rejections.

Examples of allergic, infectious and toxin-triggered andischemia-triggered diseases are: sarcoidosis, asthma, hypersensitivepneumonitis, sepsis, septic shock, endotoxin shock, toxic shocksyndrome, toxic liver failure, ARDS (acute respiratory distresssyndrome), eclampsia, cachexia, acute viral infections (e.g.,mononucleosis, fulminant hepatitis), and post-reperfusion organ damage.

An example of a pharmacologically triggered inflammation withpathophysiological relevance is the “first dose response” afteradministration of anti-T-cell antibodies such as OKT3.

An example of systemic inflammation reactions of an origin that is asyet unclear is eclampsia.

Examples of neuroinflammatory diseases that are associated with amicroglia activation are AIDS dementia, amyotrophic lateral sclerosis,Creutzfeldt-Jakob disease, Down's syndrome, diffuse Lewy body disease,Huntington's disease, leukoencephalopathy, multiple sclerosis,Parkinson's disease, Pick's disease, Alzheimer's disease, stroke,temporary lobe epilepsy and tumors. The invention therefore also relatesto the use of the indicated benzimidazole derivatives for treating thesediseases as well as for preventing these diseases.

The action of the benzimidazole derivatives according to the inventionin the treatment and prevention of microglia-associated diseases issurprising, since to date benzimidazole derivatives had been describedonly for the treatment of thromboses and arteriosclerosis [EP 0 531 883A1, EP 0 104 727 A1, WO 97/12613 A1], cystitis [WO 97/33873 A1] anddiseases that are associated with a β-amyloid peptide [U.S. Pat. No.5,552,426] as well as an increased activation of Ca-channels [EP 0 520200 A2], but an effect on microglia is not known.

Example 45 describes how the inhibition of the microglia activation canbe measured. In this case, the activation of the microglia can becarried out by various stimuli, such as with, for example, Aβ-peptide[β-Amyloid, Araujo, D. M. and Cotman, C. M., Brain Res., 569, 141-145(1992)], with prion protein, cytokines or by cell fragments [Combs, C.K. et al., J. Neurosci., 19, 928-939, (1999), Wood, P. L.,Neuroinflammation: Mechanisms and Management, Humana Press, (1998)].

The stimulation with the Aβ-peptide corresponds to thepathophysiological situation in Alzheimer's disease. In this test, thesubstances according to the invention showed inhibition of microgliaactivation in the case of stimulation with the Aβ-peptide. Theinhibition of the microglia activation by the substances according tothe invention results in a strong reduction of the cytokine productionand secretion, e.g., of II1β and TNFα (measured by ELISA and mRNAexpression analysis) and in a reduced secretion of reactiveoxygen/nitrogen intermediate products. Several inflammation factors arethus equally inhibited.

The in-vivo effectiveness of the substances according to the inventionis shown in an MCAO model in rats. This model simulates the condition ofa stroke. The substances according to the invention reduce the microgliaactivation, which occurs in the case of acute cerebral lesions in thebrains of animals.

The inhibition of cytokine production is represented, for example, bymeasuring TNFα and interleukin 12 in lipopolysaccharide (LPS)-stimulatedTHP-1 cells.

The compounds according to the invention inhibit the TNFα andinterleukin 12 production in lipopolysaccharide (LPS)-stimulated THP-1cells. To show the influence of the substances on the T-cell activation,for example, the measurement of the INFγ secretion is used. Thecompounds according to the invention inhibit the INFγ production ofperipheral mononuclear blood cells.

The invention also relates to pharmaceutical agents that contain one ormore compounds of general formula I according to the invention as wellas one or more vehicles. The pharmaceutical agents or compositions ofthe invention are produced in a way that is known in the art with thecommonly used solid or liquid vehicles or diluents and the commonly usedpharmaceutical and technical adjuvants corresponding to the desired typeof administration with a suitable dosage. The preferred preparationsconsist of a form for dispensing that is suitable for oral, enteral orparenteral, for example i.p. (intraperitoneal), i.v. (intravenous), i.m.(intramuscular) or percutaneous, administration. Such forms fordispensing are, for example, tablets, film tablets, coated tablets,pills, capsules, powders, creams, ointments, lotions, liquids, such assyrups, gels, injectable liquids, for example for i.p., i.v., i.m. orpercutaneous injection, etc. In addition, depot forms, such asimplantable preparations, as well as suppositories, are also suitable.In this case, depending on their type, the individual preparationsrelease to the body the derivatives according to the invention graduallyor all at once in a short time.

For oral administration, capsules, pills, tablets, coated tablets andliquids or other known oral forms for dispensing can be used aspharmaceutical preparations. In this case, the pharmaceutical agents canbe formulated in the way that they release the active ingredients eitherin a short time and pass on to the body or have a depot action, so thata longer-lasting, slow supply of active ingredients to the body isachieved. In addition to at least one benzimidazole derivative, thedosage units can contain one or more pharmaceutically compatiblevehicles, for example substances for adjusting the rheology of thepharmaceutical agent, surfactants, solubilizers, microcapsules,microparticles, granulates, diluents, binders, such as starches, sugar,sorbitol and gelatins, also fillers, such as silicic acid and talc,lubricants, dyes, perfumes and other substances.

Corresponding tablets can be obtained, for example, by mixing activeingredient with known adjuvants, for example inert diluents such asdextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosivessuch as corn starch or alginic acid, binders such as starch or gelatin,lubricants such as carboxypolymethylene, carboxy methyl cellulose,cellulose acetate phthalate or polyvinyl acetate. The tablets can alsoconsist of several layers.

Coated tablets can be produced accordingly by coating cores that areproduced analogously to the tablets with agents that are commonly usedin coated tablet coatings, for example polyvinylpyrrolidone or shellac,gum arabic, talc, titanium oxide or sugar. In this case, the shell ofthe coated tablet can also consist of several layers, whereby theadjuvants that are mentioned above in the case of the tablets can beused.

Capsules that contain active ingredients can be produced, for example,by the active ingredient being mixed with an inert vehicle such aslactose or sorbitol and encapsulated in gelatin capsules.

The benzimidazole derivatives according to the invention can also beformulated in the form of a solution, which is intended for oraladministration and which in addition to the active benzimidazolederivative contains as components a pharmaceutically compatible oiland/or a pharmaceutically compatible lipophilic surfactant and/or apharmaceutically compatible hydrophilic surfactant and/or apharmaceutically compatible water-miscible solvent.

To achieve better bio-availability of the active ingredients accordingto the invention, the compounds can also be formulated as cyclodextrinclathrates. To this end, the compounds are reacted with α-, β- orγ-cyclodextrin or derivatives thereof.

If creams, ointments, lotions and liquids that can be applied topicallyare to be used, the latter must be constituted so that the compoundsaccording to the invention are fed to the body in adequate amounts. Inthese forms for dispensing, adjuvants are contained, for examplesubstances for adjusting the rheology of pharmaceutical agents,surfactants, preservatives, solubilizers, diluents, substances forincreasing the permeability of the benzimidazole derivatives accordingto the invention through the skin, dyes, perfumes and skin protectionagents, such as conditioners and moisturizers. Together with thecompounds according to the invention, other active ingredients can alsobe contained in the pharmaceutical agent [Ullmanns Enzyklopädie dertechnischen Chemie [Ullmanns' Encyclopedia of Technical Chemistry],Volume 4 (1953), pages 1-39; J. Pharm. Sci., 52, 918 ff. (1963); issuedby Czetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete[Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind., 2, 72 ff(1961); Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie,Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants forPharmaceutics, Cosmetics and Related Fields], Cantor A G,Aulendorf/Württ., 1971].

The substances according to the invention can also be used in suitablesolutions such as, for example, physiological common salt solution, asinfusion or injection solutions. For parenteral administration, theactive ingredients can be dissolved or suspended in a physiologicallycompatible diluent. As diluents, in particular oily solutions, such as,for example, solutions in sesame oil, castor oil and cottonseed oil, aresuitable. To increase solubility, solubilizers, such as, for example,benzyl benzoate or benzyl alcohol, can be added.

To formulate an injectable preparation, any liquid vehicle can be usedin which the compounds according to the invention are dissolved oremulsified. These liquids frequently also contain substances to regulateviscosity, surfactants, preservatives, solubilizers, diluents and otheradditives, with which the solution is set to isotonic. Other activeingredients can also be administered together with the benzimidazolederivatives.

It is also possible to incorporate the substances according to theinvention in a transdermal system and thus to administer themtransdermally. To this end, the benzimidazole derivatives are applied inthe form of a depot injection or an implant preparation, for examplesubcutaneously. Such preparations can be formulated in such a way that adelayed release of active ingredients is made possible. To this end,known techniques can be used, for example depots that dissolve oroperate with a membrane. Implants can contain as inert materials, forexample, biodegradable polymers or synthetic silicones, for examplesilicone gum. The benzimidazole derivatives can also be incorporated in,for example, a patch, for percutaneous administration.

The dosage of the substances of general formula I according to theinvention is determined by the attending physician and depends on, i.a.,the substance that is administered, the method of administration, thedisease that is to be treated and the severity of the disease. The dailydose is no more than 1000 mg, preferably no more than 100 mg, wherebythe dose can be given as a single dose to be administered once ordivided into two or more daily doses.

1-Aryl-2N-, —S— or —O-substituted benzimidazoles (G, H, K, L, N, P)—seediagrams 2 to 4—are accessible in various ways according to processesthat are known in the literature per se.

As possible processes, in addition to others, the following can bementioned:

By reaction of arylamines (B) with ortho-leaving group-substituted,preferably halogen-substituted nitrobenzene derivatives (A),N-aryl-2-nitrobenzenes (C) can be produced under various reactionconditions, such as, for example, by heating the reactants with orwithout a suitable inert solvent, such as, for example, alkyl orhalo-benzenes. The amine that is used as reactant can also be used inexcess as a solvent. The reactions are performed both without and withbases, for example potassium carbonate or sodium hydride. Otheradjuvants, such as, for example, copper salts, are also used. Examplesof the procedures that are indicated here are found in numerous works,such as, for example, in: D. Jerchel, H. Fischer, M. Graft, Ann. Chem.575, 162 (1952), CAS, 53 (2138); R.-A. Abramovitch, Can. J. Chem., 38,2273 (1960). The nitro group (C→D) is preferably reduced byhydrogenation in polar solvents, such as acetic acid, lower alcohols orethyl acetates, with the addition of catalysts, such as Raney nickel orpalladium on carbon, or by chemical reduction, for example with tin inhydrochloric acid, SnCl₂ [F. D. Bellamy, Tet. Lett. (1984)] or Fe/aceticacid [D. C. Owsily, J. J. Bloomfield, Synthesis, 118, 150 (1977)].

[Key:]

-   Reduktion=reduction-   X=Abgangsgruppe=Leaving group-   R=Substituent(en) oder H=Substituent(s) or H    [Key:]-   Harnstoff=urea-   Alkylisothiocyanat=alkylisothiocyanate-   Arylisocyanid-dichlorid=arylisocyanide-dichloride-   Mel oder Hg(II)-Salz=Mel or Hg(II) salt.

The thus obtained diaminobenzenes of type D can be converted in variousways to 1-aryl-2N-, —S— or —O-substituted benzimidazoles (G, H, K, L, N,P):

By reaction of diamines of type D with carboxylic acid derivatives, suchas, for example, urea [H. Goeker, G. Ayhan-Kilcigil, M. Tuncbilek, C.Kus, R. Ertan, E. Kendi, S. Oezbey, M. Fort, C. Garcia, A. Farre, J.Heterocycles, 1999, 2561], benzimidazolones of type E can be produced,whose treatment with phosphorus oxychloride [M. J. Kukla, H. J. Breslin,C. J. Diamond, P. P. Grous, C. Y. Ho et al., J. Med. Chem., 1991, 3187;J. Turner; J. Chem. Soc. 1950, 1515] yields 2-chlorobenzimidazoles oftype F. The reaction of these benzimidazoles with primary or secondaryamines [M. J. Kukla, H. J. Breslin, C. J. Diamond, P. P. Grous, C. Y. Hoet al., J. Med. Chem., 1991, 3187; Efros et al., Zh. Obshch. Khim.,1953, 1691; J. Turner, J. Chem. Soc., 1950, 1515; Z. Zhu, B. Lippa, J.C. Drach, L. B. Townsend, J. Med. Chem., 2000, 2430; H. Goeker, G.Ayhan-Kilcigil, M. Tuncbilek, C. Kus, R. Erlan, E. Kendi, S. Oezbey, M.Fort, C. Garcia, A. Farre, J. Heterocycles, 1999, 2561; J. Musco, D. B.Murphy, J. Org. Chem., 1971, 3469] results in 2-amino-substitutedbenzimidazoles of types G and H. The benzimidazoles of type G can alsobe reacted to form benzimidazoles H by base-mediated alkylation [K.Kubo, Y. Kohara, E. Imamiya, Y. Sugiura, Y. Inada et al., J. Med. Chem.,1993, 2182]. Benzimidazoles of type G are also accessible, for example,in that phenylenediamines of type D are reacted with alkyl- orarylisothiocyanates to form thiourea derivatives I, which accompany acyclization to benzimidazoles G in the case of subsequent treatment withmethyl iodide [M. J. Kukla, H. J. Breslin, C. J. Diamond, P. P. Grous,C. Y. Ho et al., J. Med. Chem., 1991, 3187] or with mercury(II) salts[F. Merchan, J. Garin, V. Martinez, E. Melendez, Synthesis, 1982, 482;K. C. Nicolaou, J. I. Trujillo, B. Jandeleit, K. Chibale, M. Rosenfeldet al., Bioorg. Med. Chem., 1998, 1185]. The reaction ofphenylenediamines of type D with arylisocyanide dichlorides [J. Musco,D. B. Murphy, J. Org. Chem., 1971, 3469] represents another access tobenzimidazoles of type G.

[Key:]

-   Tetraalkyl-orthocarbonat=tetraalkyl-orthocarbonate

From the diamines of type D, 2-alkoxybenzimidazoles (K) are accessibleby, for example, reaction with tetraalkyl-orthocarbonates [M. J. Kukla,H. J. Breslin, C. J. Diamond, P. P. Grous, C. Y. Ho et al., J. Med.Chem., 1991, 3187; Y. Abe, H. Kayakiri, S. Satoh, T. Inoue, Y. Sawada etal., J. Med. Chem., 1998, 4062]. 2-Aryloxybenzimidazoles (L) can beproduced by, for example, base-mediated reaction of phenols with2-chlorobenzimidazoles (F) [M. V. Kulkami, V. D. Patil., Arch. Pharm.,1981; 440].

[Key:]

-   Alkylhalogenid=alkyl halide

From 2-chlorobenzimidazole derivatives (F), 2-arylmercaptobenzimidazoles(N) can be produced by treatment with arylthiols and bases [K. Hirai, H.Koike, T. Ishiba, S. Ueda, I. Makino et al., Eur. J. Med. Chem. Chim.Ther., 1991, 143]. These 2-arylthiobenzimidazoles are also accessible byphenylenediamines of type D being cyclized with, for example,trialkylorthoformates [A. J. Freyer, C. K. Lowe-Ma, R. A. Nissan, W. S.Wilson, Aust. J. Chem., 1992, 525] or with formic acid [S. Abuzar, S.Sharma, Z. Naturforsch. B Anorg. Chem. Org. Chem., 1981, 108] to form2-unsubstituted benzimidazoles (M) and these benzimidazoles then beingdeprotonated with strong bases and reacted with diaryl disulfides [S.Ohta et al., J. Chem. Soc. Perkin Trans., 1, 2001, 429].2-Alkylmercaptobenzimidazoles (P) are accessible, for example, in thatphenylenediamines of type D are cyclized with carbon disulfide to form2-mercaptobenzimidazoles (O) [E. R. Lavagnino, D. C. Thompson, J.Heterocycl. Chem., 1972, 149; E. L. Ellsworth, J. Domagala, J. V. N.Prasad, S. Hagen, D. Ferguson et al., Bioorg. Med. Chem. Lett.; 1999,2019], which then are reacted by base-mediated S-alkylation [E. Nicolai,J. Goyard, T. Benchetrit, J.-M. Teulon, F. Caussade et al., J. Med.Chem., 1993, 1176] to form the 2-alkylmercapto-benzimidazoles (P). The2-arylmercapto- and 2-alkylmercaptobenzimidazoles (N) and (P) can beconverted according to known processes, for example by reaction withm-chloroperbenzoic acid, into sulfoxides [J. C. Sih, W. B. Im, A.Robert, D. R. Graber, D. P. Blakeman, J. Med. Chem., 1991, 1049; S. C.Yoon, K. Kim, J. Org. Chem., 1996, 793] or sulfones [D. E. Beattie, R.Crossley, K. H. Dickinson, M. Dover, Eur. J. Med. Chem. Chim. Ther.,1983, 277-285].

For one skilled in the art, it goes without saying that substituents Rmust be compatible with the reagents that are used during the course ofthe synthesis sequence and under the reaction conditions. Thesubstituents optionally can be modified later.

Finally, it can be mentioned that in some cases, the possibility ofdirect N-arylation of pre-fabricated benzimidazoles exists, for example,according to M. J. Sansone, M. S. Kwiatek, U.S. Pat. No. 4,933,397 or D.M. T. Chan, K. L. Monaco, R.-P. Wang, M. P. Winters, Tet. Lett., 39(1998) 2933 or A. P. Combs, S. Saubem, M. Rafalski, P. Y. S. Lam, Tet.Lett., 40 (1999) 1623.

If structural element B-A-Y (Formula I) is established in protected orunprotected form because of incompatibility with the reaction conditionsduring the respective benzimidazole synthesis or for other reasons ofsynthesis only after completion of benzimidazole synthesis, variousprocedures for establishing the B-A-Y structural element (Formula I) arepossible depending on substituents R³ that are entrained in the benzenering of the benzimidazole skeleton, whereby, which is obvious to oneskilled in the art, a compatibility of the methods used with the arylsubstituents and other radicals R³ must be taken into consideration.

Below, some possibilities for establishing the B-A-Y structural elementare indicated:

Oxygen can be entrained from the start in free form or else in protectedform, for example as alkyl ether [cf, for example: B. D. Jerchel, H.Fischer, M. Graft, Ann. Chem., 575, 162 (1952)] as a substituent in abenzimidazole synthesis. By alkyl ether cleavage, for example withconcentrated hydrobromic acid with the optional aid of solubilizers suchas halogenated hydrocarbons or else with boron tribromide in inertsolvents, such as, for example, dichloromethane, the hydroxyl group canbe released. The hydroxyl group can be reacted according to knownmethods with optionally one terminal group B (Formula I) or alkyl- andallyl halides that contain a precursor thereof to form the ethers,whereby the reaction is carried out with the alkylating agentspreferably in polar solvents, such as, for example, dimethylformamide,dimethyl sulfoxide, ethers, such as, for example, tetrahydrofuran orelse lower ketones, such as acetone or methylethyl ketone, with theaddition of bases, such as alkali and alkaline-earth hydrides, butpreferably sodium hydride, or with the addition of alkali carbonates,such as potassium or cesium carbonate, in a temperature range of 0° C.to 120° C. In addition, a reaction can be carried out in a two-phasesystem under phase transfer catalysis, whereby the reactants aredissolved in a suitable inert organic solvent, such as, for example, inhaloalkanes, but preferably in dichloromethane. The other phase is asolid alkali hydroxide, preferably sodium or potassium hydroxide, orelse a concentrated aqueous solution of the hydroxide in question. Asphase transfer catalysts, for example, quaternary ammonium salts areused. Reactions under phase transfer catalysis are preferably carriedout at room temperature.

For example, a phenol derivative is dissolved in dimethylformamide andreacted to form a compound of Formula I with the addition of cesiumcarbonate with 6-bromohexanoic acid methyl ester at temperatures of 0°C. to 50° C. The cleavage of the ester by acidic or alkaline hydrolysiscan be carried out according to methods that are known to one skilled inthe art, such as, for example, with basic catalysts, such as, forexample, with alkali or alkaline-earth carbonates or -hydroxides in analcohol or the aqueous solution of an alcohol. As alcohols, aliphaticalcohols, such as, for example, methanol, ethanol, butanol, etc., areconsidered, but preferably methanol. Aqueous solutions of ethers, suchas tetrahydrofuran, are also used. As alkali carbonates and alkalihydroxides, lithium, sodium and potassium salts can be mentioned.Preferred are the lithium and sodium salts. As alkaline-earth carbonatesand hydroxides, for example, calcium carbonate, calcium hydroxide andbarium carbonate are suitable. The reaction is generally carried out at−10° C. to 70° C., but preferably at 25° C. The ester cleavage can alsobe carried out, however, under acidic conditions, such as, for example,in aqueous hydrochloric acid, optionally with the aid of a solubilizer,such as, for example, a lower alcohol, preferably methanol.

In addition, the alkylating reagents in addition to the halogen atom cancarry, as another functional group, a tetrazole in protected form, forexample tritylated, from which then after alkylation, the tetrazole isreleased. From a nitrile that is present in the alkylating reagent orelse generated later, a tetrazole can also be produced later. To thisend, the alkylating product is reacted with an azide, such as, forexample, tributyltin azide or sodium azide in a suitable solvent, suchas, for example, in aromatic hydrocarbons by heating. Also, a nitrilecan be converted by hydrolysis into a carboxylic acid group. Thealkylating reagents can also contain functional groups, such as, forexample, hydroxyl functions in free or protected form, which can beexchanged after conversion into leaving groups, such as, for example,tosylate, mesylate, bromide or iodide, for example, for cyanides,amines, alkyl, aryl or heteroaryl components. Also, the alkylatingreagents can contain functional groups, such as, for example, halogensor optionally protected amino or mercapto groups.

The introduction of nitrogen can be carried out, for example, bynitrobenzimidazoles, which are accessible according to processes thatare known in the literature [see, for example: K. Bougrin, M. Soufiaoui,Tet. Lett., 36, 21, 1995, 3683-3686; J. J. V. Eynde, F. Delfosse, P.Lor, Y. V. Haverbeke, Tetrahedron, 51, 20, 1995, 5813-5818; Q. Sun, B.Yan, Bioorg. Med. Chem. Lett., 1998, 361-364; Sandera et al., J. Amer.Chem. Soc. 76, 1954, 5173], being N-arylated at the nitrogen of thebenzimidazole (see above) and then the nitro group being reduced by, forexample, hydrogenation in polar solvents, such as acetic acid, loweralcohols or ethyl acetates, with the addition of catalysts, such asRaney nickel or palladium on carbon, or by chemical reduction with, forexample, tin in hydrochloric acid or SnCl₂ (see above) to the aminogroup. Such established amino groups then can be mono- or bis-alkylatedanalogously to the hydroxy groups (see above) with alkyl halides, suchas, for example, with ω-bromoalkanoic acid esters or converted intosulfonamides according to processes that are known in the literature. Itis also possible, for example according to standard processes, toacylate the N-monoalkylated aminobenzimidazoles with acid derivatives,such as, for example, acid anhydrides or acid halides, or to convertwith sulfonic acid anhydrides or sulfonic acid halides to thecorresponding sulfonic acid amides.

N-Aryl-2-nitrobenzenes (C), in which R stands for Cl or F, such as, forexample, (5-chloro-2-nitrophenyl)phenylamine, can also be converted byreaction with primary or secondary amines into the correspondingamine-substituted N-aryl-2-nitrobenzenes [see, for example: D. Evans, T.A. Hicks, W. R. N. Williamson, W. Dawson, S.C. R. Meacock, E. A.Kitchen, Eur. J. Med. Chem. Chim. Ther., 31, 7-8, 1996, 635-642]. Afterreduction of the nitro group and ring closure in the benzimidazole (cf.Diagrams 2-4), amine-substituted benzimidazoles of types G, H, K, L, Nand P can be obtained.

Depending on the substitution provided, substituents R³ are contained inthe synthesis components from the start or are established if necessaryat suitable sites of the synthesis sequence in question or are generatedfrom suitable precursors that are entrained. Thus, nitro groups that areentrained can be reduced to the corresponding amines according toprocesses that are already described above and converted intocarboxyamino groups.

Sulfonylamino groups are accessible from the amino compounds accordingto standard processes. Thus, for example, an amine or its hydrochlorideis reacted in a suitable inert solvent, such as an aromatic hydrocarbon,for example toluene, or a haloalkane, for example, dichloromethane, withthe aid of a base, such as, for example, triethylamine or pyridine, witha sulfonic acid halide at 0° C. to 120° C. Nitriles can be converted,for example, with Grignard reagents or lithium organyls into ketones orhydrolyzed into acids or amides. It is obvious to one skilled in the artthat the reaction conditions that are used here must be compatible withthe remaining groups that are found in the molecule.

The free acid derivatives of Formula I can be converted according todiverse processes that are known in the literature into amidederivatives or ester derivatives of Formula I.

The free acid derivatives of Formula I can also be converted withneutralization to salts with suitable amounts of the correspondinginorganic bases. For example, when the corresponding acids are dissolvedin water, which contains stoichiometric amounts of the base, the solidsalt is obtained after the water is evaporated or after a water-misciblesolvent, for example alcohol or acetone, is added.

The amine salts are produced in the usual way. To this end, thecorresponding acid is dissolved in a suitable solvent, such as, forexample, ethanol, acetone, diethyl ether or benzene, and one to fiveequivalents of the respective amine is added to this solution. In thiscase, the salt usually accumulates in solid form or is isolated afterthe solvent is evaporated in the usual way.

The clathrates with α-, β- or γ-cyclodextrin are obtained analogously tothe instructions in WO-A-87/05294. β-Cyclodextrin is preferably used.

Liposomes are produced according to the process that is described inPharmazie in unserer Zeit [Pharmaceutics in Our Time], 11, 98 (1982).

The benzimidazole derivatives according to the invention are producedanalogously to known processes: Processes for their production aredescribed in, for example, EP 0 531 883 A1. If the production of thestarting compounds is not described, the starting compounds are knownand commercially available, or the compounds are synthesized analogouslyto the described processes. Below, the production of several precursors,intermediate products and products is described by way of example.

In the production of the substances according to the invention, forexample, the following processes are used:

General Operating Instructions 1:

Reduction of Nitro Groups

The compound that is to be hydrogenated is dissolved in ethyl acetate,tetrahydrofuran, or ethanol or mixtures of the solvent, and it ishydrogenated to 2 to 5% (relative to the nitro compound) palladium oncarbon (10%) at normal pressure. After hydrogen absorption has ended, itis suctioned off, the residue is washed with ethyl acetate or ethanol,and the filtrate is concentrated by evaporation in a vacuum. The crudeproduct is reacted generally without further purification.

General Operating Instructions 2:

Alkylation of Phenol Derivatives with Alkyl Halides

A solution of 1.85 mmol of the phenol derivative in 12 ml ofN,N-dimethylformamide is mixed with 1.85 mmol of cesium carbonate and2.24 mmol of alkyl iodide. It is stirred for 12 to 96 hours, then pouredonto water, taken up with ethyl acetate, the organic phase is washedfour times with water, the latter is dried on sodium sulfate andconcentrated by evaporation in a vacuum.

As an alternative to this aqueous working-up, the reaction mixture canbe mixed with dichloromethane, separated from the precipitating salts byfiltration and the filtrate concentrated by evaporation in a vacuum.

Independently of the working-up method, the residue is purified bycrystallization or column chromatography on silica gel.

General Operating Instructions 3:

Saponification of Carboxylic Acid Alkyl Esters

0.77 mmol of the carboxylic acid alkyl ester is dissolved in 5 ml ofmethanol and 5 ml of tetrahydrofuran, and it is mixed with 5 ml of a0.5N aqueous lithium or sodium hydroxide solution. After 2 to 12 hoursof stirring, it is concentrated by evaporation in a vacuum to a verylarge extent, neutralized by the addition of aqueous hydrochloric acidand extracted with ethyl acetate. It is dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is purified, ifnecessary, by column chromatography on silica gel or by crystallization.

General Operating Instructions 4:

Conversion of Carboxylic Acid Esters to Carboxylic Acid Amides

0.36 mmol of an amine is dissolved in 3 ml of toluene and mixed drop bydrop with 0.18 ml of a 2 M solution of trimethylaluminum in toluenewhile being cooled in an ice bath. It is mixed with a solution thatconsists of 0.33 mmol of carboxylic acid methyl ester in 3 ml oftoluene, and it is stirred for 2 to 8 hours at 95° C. For working-up,water is added after cooling, it is extracted three times with ethylacetate, the combined organic phases are washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by columnchromatography on silica gel.

TABLE 1 Benzimidazole Derivatives According to the Invention No.Benzimidazole derivative 16-[[1-Phenyl-2-propylmercapto-1H-benzimidazol-6- yl]oxy]hexanoic acidmethyl ester 2 6-[[1-Phenyl-2-propanesulfinyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 36-[[1-Phenyl-2-propanesulfonyl-1H-benzimidazol-6- yl]oxy]hexanoic acidmethyl ester 46-[[1-(4-Methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 56-[[1-(4-Methylphenyl)-2-propanesulfinyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 66-[[1-(4-Methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 76-[[2-Benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 86-[[1-(4-Methylphenyl)-2-(phenylmethanesulfinyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 96-[[1-(4-Methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 106-[[1-(4-Methylphenyl)-2-(2-pyridinyl)mercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 11N-(3-Methoxypropyl)-6-[[1-(4-methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanamide 12N-(3-Methoxypropyl)-6-[[1-(4-methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanamide 13N-(3-Methoxypropyl)-6-[[2-benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy] 14N-(3-Methoxypropyl)-6-[[1-(4-methylphenyl)-2-(-phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanamide 156-[[2-(Morpholin-4-yl)-1-phenyl-1H-benzimidazol-6- yl]oxy]hexanoic acidmethyl ester 16 6-[[2-(Piperidin-1-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 176-[[1-(4-Methylphenyl)-2-(morpholin-4-yl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 186-[[1-(4-Methylphenyl)-2-(piperidin-1-yl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 19N-(3-Methoxypropyl)-6-[[2-(morpholin-4-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanamide 20N-(3-Methoxypropyl)-6-[[2-(piperidin-1-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanamide 216-[[2-Methoxy-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methylester 22 6-[[2-Methoxy-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid23 6-[[2-Ethoxy-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methylester 24 6-[[2-Ethoxy-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid 256-[[1-Phenyl-2-phenylamino-1H-benzimidazol-6-yl]oxy]hexanoic acid methylester 26 6-[[1-Phenyl-2-phenylamino-1H-benzimidazol-6-yl]oxy]hexanoicacid 27 6-[[1-(4-Methylphenyl)-2-phenylamino-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 286-[[1-Phenyl-2-propylamino-1H-benzimidazol-6-yl]oxy]hexanoic acid methylester 29 6-[[1-Phenyl-2-propylamino-1H-benzimidazol-6-yl]oxy]hexanoicacid 30 6-[[2-(N-Methyl-N-propyl)amino-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 316-[[1-(4-Methylphenyl)-2-phenyloxy-1H-benzimidazol-6- yl]oxy]hexanoicacid 32 6-[[1-(4-Methylphenyl)-2-phenylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 336-[[1-(4-Methylphenyl)-2-(phenylsulfinyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 346-[[1-(4-Methylphenyl)-2-(phenylsulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 356-[[1-Phenyl-2-propylmercapto-1H-benzimidazol-6- yl]oxy]hexanoic acid 366-[[1-Phenyl-2-propanesulfonyl-1H-benzimidazol-6- yl]oxy]hexanoic acid37 6-[(2-Benzylmercapto-1-phenyl-1H-benzimidazol-6- yl)oxy]hexanoic acidmethyl ester 386-[[1-Phenyl-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester 396-[(2-Benzylmercapto-1-phenyl-1H-benzimidazol-6- yl)oxy]hexanoic acid 406-[[1-Phenyl-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid 416-[[1-(4-Methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid 426-[[1-(4-Methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoic acid 436-[[2-Benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid 446-[[1-(4-Methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]-hexanoic acid

TABLE 2 Benzimidazole Derivatives According to the Invention II

Nr. R¹ Z—R² B 1 Phenyl S—(CH₂)₂CH₃ COOCH₃ 2 Phenyl SO—(CH₂)₂CH₃ COOCH₃ 3Phenyl SO₂—(CH₂)₂CH₃ COOCH₃ 4 p-CH₃-Phenyl S—(CH₂)₂CH₃ COOCH₃ 5p-CH₃-Phenyl SO—(CH₂)₂CH₃ COOCH₃ 6 p-CH₃-Phenyl SO₂—(CH₂)₂CH₃ COOCH₃ 7p-CH₃-Phenyl S—CH₂Phenyl COOCH₃ 8 p-CH₃-Phenyl SO—CH₂Phenyl COOCH₃ 9p-CH₃-Phenyl SO₂—CH₂Phenyl COOCH₃ 10 p-CH₃-Phenyl S-2-Pyridiny COOCH₃ 11p-CH₃-Phenyl S—(CH₂)₂CH₃ CONH(CH₂)₃OCH₃ 12 p-CH₃-Phenyl SO₂—(CH₂)₂CH₃CONH(CH₂)₃OCH₃ 13 p-CH₃-Phenyl S—CH₂Phenyl CONH(CH₂)₃OCH₃ 14p-CH₃-Phenyl SO₂—CH₂Phenyl CONH(CH₂)₃OCH₃ 15 Phenyl 4-Morpholinyl COOCH₃16 Phenyl 1-Piperidyl COOCH₃ 17 p-CH₃-Phenyl 4-Morpholinyl COOCH₃ 18p-CH₃-Phenyl 1-Piperidyl COOCH₃ 19 Phenyl 4-Morpholinyl CONH(CH₂)₃OCH₃20 Phenyl 1-Piperidyl CONH(CH₂)₃OCH₃ 21 Phenyl O—CH₃ COOCH₃ 22 PhenylO—CH₃ COOH 23 Phenyl O—CH₂CH₃ COOCH₃ 24 Phenyl O—CH₂CH₃ COOH 25 PhenylNH-Phenyl COOCH₃ 26 Phenyl NH-Phenyl COOH 27 p-CH₃-Phenyl NH-PhenylCOOCH₃ 28 Phenyl NH—(CH₂)₂CH₃ COOCH₃ 29 Phenyl NH—(CH₂)₂CH₃ COOH 30Phenyl N(CH₃)(CH₂)₂CH₃ COOCH₃ 31 p-CH₃-Phenyl O-Phenyl COOH 32p-CH₃-Phenyl S-Phenyl COOCH₃ 33 p-CH₃-Phenyl SO-Phenyl COOCH₃ 34p-CH₃-Phenyl SO₂-Phenyl COOCH₃ 35 Phenyl S—(CH₂)₂CH₃ COOH 36 PhenylSO₂—(CH₂)₂CH₃ COOH 37 Phenyl S—CH₂Phenyl COOCH₃ 38 Phenyl SO₂—CH₂PhenylCOOCH₃ 39 Phenyl S—CH₂Phenyl COOH 40 Phenyl SO₂—CH₂Phenyl COOH 41p-CH₃-Phenyl S—(CH₂)₂CH₃ COOH 42 p-CH₃-Phenyl SO₂—(CH₂)₂CH₃ COOH 43p-CH₃-Phenyl S—CH₂Phenyl COOH 44 p-CH₃-Phenyl SO₂—CH₂Phenyl COOH

EXAMPLE 16-[[1-Phenyl-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid-methyl ester

a) 3-Phenylamino-4-nitrophenol

14 g of 3-fluoro-4-nitrophenol and 24 ml of aniline were mixed andstirred for 3 hours at 140° C. After cooling, it was dissolved in ethylacetate and extracted six times with 2N aqueous hydrochloric acid. Theorganic phase was washed with saturated sodium chloride solution, driedon sodium sulfate, concentrated by evaporation in a vacuum, and theresidue was crystallized from diisopropyl ether. 20.8 g was obtained.

Flash point 170-172° C.

b) 6-(3-Phenylamino-4-nitrophenyl)oxyhexanoic acid methyl ester

13.3 g of 3-phenylamino-4-nitrophenol was reacted with 6-bromohexanoicacid methyl ester according to general operating instructions 2. 11.2 gwas obtained.

¹H-NMR (CDCl₃): δ=1.38-1.52 ppm m (2H); 1.59-1.80 m (4H); 2.33 t (J=7.5Hz, 2H); 3.67 s (3H); 3.87 t (J=7.5 Hz, 2H); 6.32 dd (J=8.2 Hz, 1H);6.52 d (J=2 Hz, 1H); 7.20-7.32 m (3H); 7.40-7.48 m (2H); 8.18 d (J=8 Hz,1H); 9.75 s (broad) (1H).

c) 6-(-3-Phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester

4.5 g of 6-(3-phenylamino-4-nitrophenyl)oxyhexanoic acid methyl esterwas reduced by reaction according to general operating instructions 1.4.3 g was obtained.

¹H-NMR (CDCl₃): δ=1.42-1.52 ppm m (2H); 1.62-1.83 m (4H); 2.34 t (J=7.5Hz, 2H); 3.68 s (3H); 3.86 t (J=7.5 Hz, 2H); 5.32 s (broad) (1H); 6.54dd (J=8.2 Hz, 1H); 6.74 d (J=8 Hz, 1H); 6.78 d (J=2 Hz, 1H); 6.80-6.90 m(3H); 7.20-7.29 m (2H).

d) 6-[[2-Mercapto-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methylester

0.4 g of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl esterwas dissolved in 5 ml of pyridine, mixed with 75 μl of carbon disulfide,and the mixture was stirred for 12 hours at 20° C. It was mixed withsaturated sodium bicarbonate solution, extracted three times with ethylacetate, the combined organic phases were washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 368 mg was obtained.

Flash point 122-123° C.

e) 6-[[1-Phenyl-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester

100 mg of 6-[[2-mercapto-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was dissolved in 2 ml of N,N-dimethylformamide, mixed with40 μl of propyl iodide, 57 mg of potassium hydrogen carbonate and 10 mgof dicyclohexano-18-crown-6, and the mixture was stirred for 15 hours at20° C. It was filtered, and the filtrate was concentrated by evaporationin a vacuum. The residue was purified by column chromatography on silicagel. 103 mg was obtained.

Flash point 45.5-47° C.

EXAMPLE 26-[[1-Phenyl-2-propanesulfinyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester

80 mg of 6-[[1-phenyl-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was dissolved in 2 ml of dichloromethane, mixed with56 mg of m-chloroperbenzoic acid (about 60%), and the mixture wasstirred for 10 minutes at 20° C. It was mixed with sodium disulfitesolution, extracted twice with dichloromethane, the combined organicphases were washed with saturated sodium bicarbonate solution, water andsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel. 30 mg was obtained.

¹H-NMR (CDCl₃): δ=1.06 ppm t (J=8 Hz, 3H); 1.43-1.55 m (2H); 1.62-1.85 m(6H); 2.33 t (J=7.5 Hz, 2H); 3.24-3.36 m (1H); 3.47-3.58 m (1H); 3.67 s(3H); 3.90 t (J=7.5 Hz, 2H); 6.67 d (J=2 Hz, 1H); 7.02 dd (J=8.2 Hz,1H); 7.50-7.69 m (5H); 7.78 d (J=8 Hz, 1H).

EXAMPLE 36-[[1-Phenyl-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester

85 mg of 6-[[1-phenyl-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was dissolved in 2 ml of dichloromethane, mixed with59 mg of m-chloroperbenzoic acid (about 60%), and the mixture wasstirred for 9 hours at 20° C. It was mixed with sodium disulfitesolution, extracted twice with dichloromethane, the combined organicphases were washed with saturated sodium bicarbonate solution, water andsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel. 30 mg was obtained.

MS (EI): 444 (molecular ion peak).

EXAMPLE 46-[[1-(4-Methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

a) 3-(4-Methylphenyl)amino-4-nitrophenol

1.3 g of 3-fluoro-4-nitrophenol and 2.7 g of 4-methylaniline were mixedand stirred for 14 hours at 140° C. After cooling, it was dissolved inethyl acetate and extracted three times with 4N aqueous hydrochloricacid. The organic phase was washed with saturated sodium chloridesolution, dried on sodium sulfate, concentrated by evaporation in avacuum, and the residue was crystallized from diisopropyl ether. 1.70 gwas obtained.

¹H-NMR (CDCl₃): δ=2.34 ppm s (3H); 6.25 dd (J=8.2 Hz, 1H); 6.48 d (J=2Hz, 1H); 7.12-7.20 m (4H); 8.08 d (J=8 Hz, 1H); 9.64 s (broad) (1H);9.72 s (broad) (1H).

b) 6-[3-(4-Methylphenyl)amino-4-nitrophenyl]oxyhexanoic acid methylester

990 mg of 3-(4-methylphenyl)amino-4-nitrophenol was reacted with6-bromohexanoic acid methyl ester according to general operatinginstructions 2. 1.5 g was obtained.

¹H-NMR (CDCl₃): δ=1.38-1.50 ppm m (2H); 1.60-1.80 m (4H); 2.33 t (J=7.5Hz, 2H); 2.39 s (3H); 3.68 s (3H); 3.85 t (J=7.5 Hz, 2H); 6.28 dd (J=8.2Hz, 1H); 6.45 d (J=2 Hz, 1H); 7.15 d (J=8 Hz, 2H); 7.24 d (J=8 Hz, 2H);8.18 d (J=8 Hz, 1H); 9.70 s (broad) (, 1H).

c) 6-[3-(4-Methylphenyl)amino-4-aminophenyl]oxyhexanoic acid methylester

1.3 g of 6-[3-(4-methylphenyl)amino-4-nitrophenyl]oxyhexanoic acidmethyl ester was reduced by reaction according to general operatinginstructions 1. 1.19 g was obtained.

¹H-NMR (CDCl₃): δ=1.40-1.54 ppm m (2H); 1.62-1.78 m (4H); 2.30 s (3H);2.33 t (J=7.5 Hz, 2H); 3.68 s (3H); 3.85 t (J=7.5 Hz, 2H); 5.27 s(broad) (1H); 6.50 dd (J=8.2 Hz, 1H); 6.72 d (J=2 Hz, 1H); 6.74 d (J=8Hz, 1H); 6.80 d (J=8 Hz, 2H); 7.04 d (J=8 Hz, 2H).

d) 6-[[2-Mercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

3 g of 6-[3-(4-methylphenyl)-4-aminophenyl]oxyhexanoic acid methyl esterwas dissolved in 15 ml of pyridine, mixed with 0.6 ml of carbondisulfide, and the mixture was stirred for 20 hours at 20° C. It wasmixed with saturated sodium bicarbonate solution, extracted three timeswith ethyl acetate, the combined organic phases were washed withsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was crystallizedfrom diisopropyl ether. 2.6 g was obtained.

¹H-NMR (CDCl₃): δ=1.40-1.52 ppm m (2H); 1.60-1.82 m (4H); 2.33 t (J=7.5Hz, 2H); 2.48 s (3H); 3.66 s (3H); 3.89 t (J=7.5 Hz, 2H); 6.46 d (J=2Hz, 1H); 6.80 dd (J=8 Hz, 1H); 7.16 d (J=8 Hz, 1H); 7.40 s (4H).

e)6-[[1-(4-Methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

1 g of6-[[2-mercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was dissolved in 15 ml of N,N-dimethylformamide, mixed with0.3 ml of propyl iodide, 0.55 g of potassium hydrogen carbonate and 97mg of dicyclohexano-18-crown-6, and the mixture was stirred for 48 hoursat 20° C. It was filtered, and the filtrate was concentrated byevaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 1.06 g was obtained.

¹H-NMR (CDCl₃): δ=1.02 ppm t (J=8 Hz, 3H); 1.43-1.52 m (2H); 1.62-1.83 m(6H); 2.32 t (J=7.5 Hz, 2H); 2.48 s (3H); 3.30 t (J=8 Hz, 2H); 3.67 s(3H); 3.90 t (J=7.5 Hz, 2H); 6.56 d (J=2 Hz, 1H); 6.83 dd (J=8.2 Hz,1H); 7.32 d (J=7.5 Hz, 2H); 7.39 d (J=7.5 Hz, 2H); 7.58d (J=8 Hz, 1H).

EXAMPLE 56-[[1-(4-Methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester EXAMPLE 66-[[1-(4-Methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

600 mg of6-[[1-(4-methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was dissolved in 10 ml of dichloromethane, mixed with405 mg of m-chloroperbenzoic acid (about 60%), and the mixture wasstirred for 15 minutes at 20° C. It was mixed with sodium disulfitesolution, extracted twice with dichloromethane, the combined organicphases were washed with saturated sodium bicarbonate solution, water andsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel. 525 mg of6-[[1-(4-methylphenyl)-2-propanesulfinyl-11H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was obtained.

¹H-NMR (CDCl₃): δ=1.05 ppm t (J=8 Hz, 3H); 1.43-1.54 m (2H); 1.62-1.78 m(6H); 2.33 t (J=7.5 Hz, 2H); 2.50 s (3H); 3.25-3.35 m (1H); 3.43-3.53 m(1H); 3.67 s (3H); 3.90 t (J=7.5 Hz, 2H); 6.62 d (J=2 Hz, 1H); 7.00 dd(J=8.2 Hz, 1H); 7.40 s (4H); 7.78 d (J=8 Hz, 1H),

and 239 mg of6-[[1-(4-methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester,

¹H-NMR (CDCl₃): δ=1.04 ppm t (J=8 Hz, 3H); 1.42-1.54 m (2H); 1.62-1.92(6H); 2.34 t (J=7.5 Hz, 2H); 2.48 s (3H); 3.48 t (J=8 Hz, 2H); 3.67 s(3H); 3.88 t (J=7.5 Hz, 2H); 6.52 d (J=2 Hz, 1H); 7.00 dd (J=8.2 Hz,1H); 7.39 s (4H); 7.76 d (J=8 Hz, 1H).

EXAMPLE 76-[[2-Benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

800 mg of6-[[2-mercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was dissolved in 8 ml of N,N-dimethylformamide, mixed with0.3 ml of benzylbromide, 438 mg of potassium hydrogen carbonate and 75mg of dicyclohexano-18-crown-6, and the mixture was stirred for 15 hoursat 20° C. It was filtered, and the filtrate was concentrated byevaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 976 mg was obtained.

MS (EI): 474 (molecular ion peak).

EXAMPLE 86-[[1-(4-Methylphenyl)-2-(phenylmethanesulfinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester EXAMPLE 96-[[1-(4-Methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

500 mg of6-[[2-benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was dissolved in 9 ml of dichloromethane, mixed with303 mg of m-chloroperbenzoic acid (about 60%), and the mixture wasstirred for 2 hours at 20° C. It was mixed with sodium disulfitesolution, extracted twice with dichloromethane, the combined organicphases were washed with saturated sodium bicarbonate solution, water andsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel. 232 mg of6-[[1-(4-methylphenyl)-2-(phenylmethanesulfinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was obtained.

¹H-NMR (CDCl₃): δ=1.42-1.53 ppm m (2H); 1.62-1.84 m (4H); 2.32 t (J=7.5Hz, 2H); 2.42 s (3H); 3.64 s (3H); 3.88 t (J=7.5 Hz, 2H); 4.58 d (J=12Hz, 1H); 4.88 d (J=12 Hz, 1H); 6.50 d (J=2 Hz, 1H); 6.75-6.93 m (2H);7.01 dd (J=8.2 Hz, 1H); 7.12 d (J=8 Hz, 2H); 7.20-7.33 m (5H); 7.82 d(J=8 Hz, 11H),

and 189 mg of6-[[1-(4-methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester,

¹H-NMR (CDCl₃): δ=1.42-1.54 ppm m (2H); 1.58-1.82 m (4H); 2.34 t (J=7.5Hz, 2H); 2.42 s (3H); 3.67 s (3H); 3.86 t (J=7.5 Hz, 2H); 4.75 s (2H);6.38 d (J=2 Hz, 1H); 6.86 d (J=8 Hz, 2H); 7.03 dd (J=8.2 Hz, 1H);7.15-7.38 m (7H); 7.82 d (J=8 Hz, 1H).

EXAMPLE 106-[[1-(4-Methylphenyl)-2-(2-pyridinyl)mercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

200 mg of6-[[1-(4-methylphenyl)-2-mercapto-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was heated to 150° C. with 80 μl of 2-chloropyridine for 14hours. After another 200 μl of 2-chloropyridine was added, it was heatedfor 3 hours to 170° C. After cooling, it was purified by columnchromatography on silica gel. 40 mg was obtained.

MS (EI): 461 (molecular ion peak).

EXAMPLE 11N-(3-Methoxypropyl)-6-[[1-(4-methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanamide

100 mg of6-[[1-(4-methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was reacted with 3-methoxypropylamine according togeneral operating instructions 4. 38 mg was obtained.

MS (EI): 483 (molecular ion peak).

EXAMPLE 12N-(3-Methoxypropyl)-6-[[1-(4-methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanamide

100 mg of6-[[1-(4-methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was reacted with 3-methoxypropylamine according togeneral operating instructions 4. 105 mg was obtained.

MS (EI): 515 (molecular ion peak).

EXAMPLE 13N-(3-Methoxypropyl)-6-[[1-(4-methylphenyl)-2-benzylmercapto-1H-benzimidazol-6-yl]oxy]hexanamide

100 mg of6-[[2-benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was reacted with 3-methoxypropylamine according togeneral operating instructions 4. 53 mg was obtained.

MS (EI): 531 (molecular ion peak).

EXAMPLE 14N-(3-Methoxypropyl)-6-[[1-(4-methylphenyl)-2(-phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexamide

100 mg of6-[[1-(4-methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was reacted with 3-methoxypropylamine according togeneral operating instructions 4. 22 mg was obtained.

MS (EI): 563 (molecular ion peak).

EXAMPLE 156-[[2-(Morpholin-4-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester

a) 6-[[1-Phenyl-2-oxo-2,3-dihydro-1H-benzoimidazol-6-yl]oxy]hexanoicacid methyl ester

7.5 g of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl esterwas mixed with 8.23 g of urea, and the mixture was heated to 140° C. for4 hours. After cooling, it was mixed with water, extracted three timeswith ethyl acetate, the combined organic phases were washed withsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was crystallizedfrom diisopropyl ether. 4.27 g was obtained.

Flash point 146.5-148° C.

b) 6-[[2-Chloro-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methylester

3 g of 6-[[1-phenyl-2-oxo-2,3-dihydro-1H-benzoimidazol-6-yl]oxy]hexanoicacid methyl ester was mixed with 12 ml of phosphorus oxychloride, andthe mixture was refluxed for 4 hours. After cooling, it was stirred intosaturated sodium bicarbonate solution, extracted three times with ethylacetate, the combined organic phases were dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel. 1.28 g was obtained.

MS (EI): 372 (molecular ion peak).

c) 6-[[2-(Morpholin-4-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

657 mg of 6-[[2-chloro-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was dissolved in 13 ml of morpholine, and the mixture wasstirred for 6 hours at 120° C. It was concentrated by evaporation to avery large extent in a vacuum, mixed with water, extracted with ethylacetate, the organic phase was dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 271 mg was obtained.

¹H-NMR (CDCl₃): δ=1.42-1.54 ppm m (2H); 1.55-1.80 (4H); 2.34 t (J=7.5Hz, 2H); 3.20 t (J=7.5 Hz, 4H); 3.66 s (3H); 3.66 t (J=7.5 Hz, 4H); 3.92t (J=7.5 Hz, 2H); 6.62 d (J=2 Hz, 1H); 6.82 dd (J=8, 2 Hz, 1H);7.45-7.61 m (6H).

EXAMPLE 166-[[2-(Piperidin-1-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester

100 mg of 6-[[2-chloro-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was dissolved in 2.5 ml of piperidine, and the mixture wasstirred for 5 hours at 100° C. It was concentrated by evaporation to avery large extent in a vacuum, mixed with water, extracted with ethylacetate, the organic phase was dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 30 mg was obtained.

¹H-NMR (CDCl₃): δ=1.42-1.57 ppm m (8H); 1.63-1.80 m (4H); 2.32 t (J=7.5Hz, 2H); 3.10-3.18 m (4H); 3.65 s (3H); 3.90 t (J=7.5 Hz, 2H); 6.62 d(J=2 Hz, 1H); 6.79 dd (J=8.2 Hz, 1H); 7.40-7.58 m (6H).

EXAMPLE 176-[[1-(4-Methylphenyl)-2-(morpholin-4-yl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

a)6-[[1-(4-Methylphenyl)-2-oxo-2,3-dihydro-1H-benzoimidazol-6-yl]oxy]hexanoicacid methyl ester

5 g of 6-[3-(4-methylphenyl)-4-aminophenyl]oxyhexanoic acid methyl esterwas mixed with 5.28 g of urea, and the mixture was heated for 5 hours to150° C. After cooling, it was mixed with water, extracted three timeswith ethyl acetate, the combined organic phases were washed withsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was crystallizedfrom diisopropyl ether. 2.54 g was obtained.

Flash point 99-100° C.

b) 6-[[2-Chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

2.5 g of6-[[1-(4-methylphenyl)-2-oxo-2,3-dihydro-1H-benzoimidazol-6-yl]oxy]hexanoicacid methyl ester was mixed with 10 ml of phosphorus oxychloride, andthe mixture was refluxed for 2 hours. After cooling, it was stirred intosaturated sodium bicarbonate solution, extracted three times with ethylacetate, the combined organic phases were dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel. 1.28 g was obtained.

¹H-NMR (CDCl₃): δ=1.42-1.54 ppm m (2H); 1.60-1.84 m (4H); 2.34 t (J=7.5Hz, 2H); 2.50 s (3H); 3.66 s (3H); 3.88 t (J=7.5 Hz, 2H); 6.58 d (J=2Hz, 1H); 6.92 d (J=8 Hz, 1H); 7.30 d (J=7.5 Hz, 2H); 7.40 d (J=7.5 Hz,2H); 7.60 d (J=8 Hz, 1H).

c)6-[[1-(4-Methylphenyl)-2-(morpholin-4-yl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

240 mg of6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was mixed with 0.2 ml of N,N-dimethylformamide and 0.7 mlof morpholine, and the mixture was stirred for 7.5 hours at 110° C.Another 0.7 ml of morpholine was added and heated for another 4 hours at110° C. It was mixed with water, extracted with ethyl acetate, theorganic phase was dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 7 mg was obtained.

¹H-NMR (CDCl₃): δ=1.42-1.53 ppm m (2H); 1.60-1.82 m (4H); 2.34 t (J=7.5Hz, 2H); 2.50 s (3H); 3.20 t (J=7.5 Hz, 4H); 3.68 s (3H); 3.68 t (J=7.5Hz, 4H); 3.90 t (J=7.5 Hz, 2H); 6.60 d (J=2 Hz, 1H); 6.80 dd (J=8.2 Hz,1H); 7.38 s (4H); 7.48 d (J=8 Hz, 1H).

EXAMPLE 186-[[1-(4-Methylphenyl)-2-(piperidin-1-yl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

240 mg of6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was mixed with 0.2 ml of N,N-dimethylformamide and 0.75 mlof piperidine, and the mixture was stirred for 7.5 hours at 110° C.Another 0.75 ml of piperidine was added, and it was heated for another 4hours at 110° C. It was mixed with water, extracted with ethyl acetate,the organic phase was dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 16 mg was obtained.

¹H-NMR (CDCl₃): δ=1.40-1.58 ppm m (8H); 1.62-1.82 m (4H); 2.32 t (J=7.5Hz, 2H); 2.48 s (3H); 3.14-3.22 m (4H); 3.68 s (3H); 3.88 t (J=7.5 Hz,2H); 6.58 d (J=2 Hz, 1H); 6.78 dd (J=8.2 Hz, 1H); 7.36 s (4H); 7.50 d(J=8 Hz, 1H).

EXAMPLE 19N-(3-Methoxypropyl)-6-[[2-(morpholin-4-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanamide

135 mg of6-[[2-(morpholin-4-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was reacted with 3-methoxypropylamine according to generaloperating instructions 4. 94 mg was obtained.

MS (EI): 480 (molecular ion peak).

EXAMPLE 20N-(3-Methoxypropyl)-6-[[2-(piperidin-1-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanamide

100 mg of6-[[2-(piperidin-1-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was reacted with 3-methoxypropylamine according to generaloperating instructions 4. 47 mg was obtained.

¹H-NMR (CDCl₃): δ=1.40-1.55 ppm m (8H); 1.60-1.80 m (4H); 2.18 t (J=7.5Hz, 2H); 3.14-3.24 m (4H); 3.36 s (3H); 3.36-3.42 m (2H); 3.45 t (J=7.5Hz, 2H); 3.90 t (J=7.5 Hz, 2H); 6.00 s (broad) (1H); 6.62 d (J=2 Hz,1H); 6.80 d (J=8.2 Hz, 1H); 7.40-7.62 m (6H).

EXAMPLE 21 6-[[2-Methoxy-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester

200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl esterwas mixed with 0.12 ml of tetramethylorthocarbonate and 40 μl of aceticacid, and the mixture was heated for 4 hours to 80° C. After cooling, itwas mixed with 1N sodium hydroxide solution, extracted three times withethyl acetate, the combined organic phases were washed with saturatedsodium chloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 104 mg was obtained.

Flash point 104-106° C.

EXAMPLE 22 6-[[2-Methoxy-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid

56 mg of 6-[[2-methoxy-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was reacted according to general operating instructions 3.33 mg was obtained.

Flash point 134-136° C.

EXAMPLE 23 6-[[2-Ethoxy-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester

200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl esterwas mixed with 0.19 ml of tetraethylorthocarbonate and 40 μl of aceticacid, and the mixture was heated for 4 hours to 80° C. After cooling, itwas mixed with 1N sodium hydroxide solution, extracted three times withethyl acetate, the combined organic phases were washed with saturatedsodium chloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 124 mg was obtained.

¹H-NMR (CDCl₃): δ=1.45 ppm t (J=8 Hz, 3H); 1.45-1.55 m (2H); 1.63-1.85 m(4H); 2.35 t (J=7.5 Hz, 2H); 3.67 s (3H); 3.95 t (J=7.5 Hz, 2H); 4.60 t(J=8 Hz, 2H); 6.72 d (J=2 Hz, 1H); 6.83 dd (J=8.2 Hz, 1H); 7.40-7.60 m(6H).

EXAMPLE 24 6-[[2-Ethoxy-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid

50 mg of 6-[[2-ethoxy-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was reacted according to general operating instructions 3.44 mg was obtained.

Flash point 127-130° C.

EXAMPLE 25 6-[[1-Phenyl-2-phenylamino-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl esterwas dissolved in 1 ml of 1,2-dichloroethane, the solution was mixed with85 μl of phenylisocyanide dichloride, and the mixture was heated for 6hours to 65° C. After cooling, it was mixed with water, extracted threetimes with ethyl acetate, the combined organic phases were washed withsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel. 55 mg was obtained.

MS (EI): 429 (molecular ion peak).

EXAMPLE 26 6-[[1-Phenyl-2-phenylamino-1H-benzimidazol-6-yl]oxy]hexanoicacid

50 mg of 6-[[1-phenyl-2-phenylamino-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was reacted according to general operatinginstructions 3. 33 mg was obtained.

Flash point 148-149.5° C.

EXAMPLE 276-[[1-(4-Methylphenyl)-2-phenylamino-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

250 mg of 6-[3-(4-methylphenyl)-4-aminophenyl]oxyhexanoic acid methylester was dissolved in 1 ml of 1,2-dichloroethane, the solution wasmixed with 0.1 ml of phenylisocyanide dichloride, and the mixture washeated for 8 hours to 65° C. After cooling, it was mixed with water,extracted three times with ethyl acetate, the combined organic phaseswere washed with saturated sodium chloride solution, dried on sodiumsulfate and concentrated by evaporation in a vacuum. The residue wascrystallized from a mixture that consists of ethyl acetate and diethylether. 147 mg was obtained.

Flash point 142-143.5° C.

EXAMPLE 28 6-[[1-Phenyl-2-propylamino-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl esterwas dissolved in 2 ml of methanol, the solution was mixed with 90 μl ofpropylisothiocyanate, and the mixture was heated for 3 hours to 50° C.After cooling, it was mixed with saturated ammonium chloride solution,diluted with water, extracted three times with ethyl acetate, thecombined organic phases were washed with saturated sodium chloridesolution, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue was purified by column chromatography on silica gel.140 mg of a thiourea derivative, which was dissolved in 1.5 ml ofmethanol, was obtained. 0.16 ml of iodomethane was added to thissolution, and it was refluxed for 4 hours. After cooling, it was mixedwith 1N aqueous hydrochloric acid, extracted three times with ethylacetate, the combined organic phases were washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 72 mg was obtained.

MS (EI): 395 (molecular ion peak).

EXAMPLE 29 6-[[1-Phenyl-2-propylamino-1H-benzimidazol-6-yl]oxy]hexanoicacid

30 mg of 6-[[1-phenyl-2-propylamino-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was reacted according to general operatinginstructions 3. 17 mg was obtained.

Flash point 123-125° C.

EXAMPLE 306-[[2-(N-Methyl-N-propyl)amino-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

20 mg of 6-[[1-phenyl-2-propylamino-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was dissolved in 1 ml of tetrahydrofuran. 10 mg ofsodium hydride (80% in mineral oil) was added, it was stirred for 30minutes at 20° C., then 50 μl of iodomethane was added at 0° C., and itwas stirred for 1 hour at 0° C. It was mixed with saturated ammoniumchloride solution, diluted with water, extracted three times with ethylacetate, the combined organic phases were washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 6 mg was obtained.

¹H-NMR (CDCl₃): δ=0.70 ppm t (J=7.5 Hz, 3H); 1.38-1.53 m (4H); 1.63-1.83m (4H); 2.31 t (J=7.5 Hz, 2H), 2.82 s (3H); 3.02 t (J=7.5 Hz, 2H); 3.67s (3H); 3.88 t (J=7.5 Hz, 2H); 6.53 d (J=2 Hz, 1H); 6.77 dd (J=8.2 Hz,1H); 7.40-7.60 m (6H).

EXAMPLE 316-[[1-(4-Methylphenyl)-2-phenyloxy-1H-benzimidazol-6-yl]oxy]hexanoicacid

150 mg of6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was dissolved in 2 ml of dimethylformamide, mixed with 54mg of potassium carbonate and 37 mg of phenol, and the mixture wasstirred for 7 days at 150° C. After cooling, it was mixed with saturatedammonium chloride solution, diluted with water, extracted three timeswith ethyl acetate, the combined organic phases were washed withsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel. 78 mg was obtained.

MS (EI): 430 (molecular ion peak).

EXAMPLE 326-[[1-(4-Methylphenyl)-2-phenylmercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

150 mg of6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was dissolved in 2 ml of dimethylformamide, mixed with 54mg of potassium carbonate and 40 μl of thiophenol, and the mixture wasstirred for 5 hours at 140° C. After cooling, it was mixed withsaturated ammonium chloride solution, diluted with water, extractedthree times with ethyl acetate, the combined organic phases were washedwith saturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. 158 mg was obtained.

¹H-NMR (CDCl₃): δ=1.40-1.52 ppm m (2H); 1.60-1.82 m (6H); 2.32 t (J=7.5Hz, 2H); 2.45 s (3H); 3.65 s (3H); 3.91 t (J=7.5 Hz, 2H); 6.52 d (J=2Hz, 1H); 6.90 dd (J=8.2 Hz, 1H); 7.10-7.44 m (9H); 7.68 d (J=8 Hz, 1H).

EXAMPLE 336-[[1-(4-Methylphenyl)-2-(phenylsulfinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester EXAMPLE 346-[[1-(4-Methylphenyl)-2-(phenylsulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

180 mg of6-[[1-4-methylphenyl)-2-phenylmercapto-1H-benzimidazol-6-yl]oxy]-hexanoicacid methyl ester was dissolved in 4 ml of dichloromethane, mixed with112 mg of m-chloroperbenzoic acid (about 55%), and the mixture wasstirred for 5 hours at 20° C. It was mixed with sodium disulfitesolution, extracted twice with dichloromethane, the combined organicphases were washed with saturated sodium bicarbonate solution, water andsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel. 56 mg of6-[[1-(4-methylphenyl)-2-(phenylsulfinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was obtained.

¹H-NMR (CDCl₃): δ=1.40-1.50 ppm m (2H); 1.60-1.80 m (6H); 2.30 t (J=7.5Hz, 2H); 2.48 s (3H); 3.64 s (3H); 3.85 t (J=7.5 Hz, 2H); 6.48 d (J=2Hz, 1H); 6.95 dd (J=8.2 Hz, 1H); 7.02-7.12 m (2H); 7.20-7.45 m (7H);7.78 d (J=8 Hz, 1H).

and 39 mg of6-[[1-(4-methylphenyl)-2-(phenylsulfonyl)-1H-benzimidazol-6-yl]oxy]-hexanoicacid methyl ester,

¹H-NMR (CDCl₃): δ=1.38-1.52 ppm m (2H); 1.60-1.80 m (6H); 2.30 t (J=7.5Hz, 2H); 2.50 s (3H); 3.64 s (3H); 3.83 t (J=7.5 Hz, 2H); 6.38 d (J=2Hz, 1H); 6.98 dd (J=8.2 Hz, 1H); 7.10 d (J=8 Hz, 2H); 7.27 d (J=8 Hz,2H); 7.43 dd (J=8.8 Hz, 2H); 7.58 m (1H); 7.72 d (J=8.8 Hz, 2H); 7.78 d(J=8 Hz, 1H).

EXAMPLE 356-[[1-Phenyl-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid

109 mg of6-[[1-phenyl-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was reacted according to general operating instructions 3with lithium hydroxide. 104 mg was obtained.

MS (EI): 398 (molecular ion peak).

EXAMPLE 366-[[1-Phenyl-2-propanesulfonyl-1H-benzimidzol-6-yl]oxy]hexanoic acid

228 mg of6-[[1-phenyl-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester was reacted with lithium hydroxide according to generaloperating instructions 3. 152 mg was obtained.

¹H-NMR (CDCl₃): δ=1.03 ppm t (J=8 Hz, 3H); 1.45-1.60 m (2H); 1.62-1.95 m(6H); 2.36 t (J=7.5 Hz, 2H); 3.45-3.56 m (2H); 3.90 t (J=7.5 Hz, 2H);6.51 d (J=2 Hz, 1H); 7.02 dd (J=8.2 Hz, 1H); 7.48-7.66 m (5H); 7.77 d(J=8 Hz, 1H).

EXAMPLE 376-[(2-Benzylmercapto-1-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acidmethyl ester

490 mg of 6-[(2-mercapto-1-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acidmethyl ester was dissolved in 7 ml of N,N-dimethylformamide, mixed with0.19 ml of benzyl bromide, 278 mg of potassium bicarbonate and 49 mg ofdicyclohexano-18-crown-6, and the mixture was stirred for 15 hours at20° C. It was filtered, and the filtrate was concentrated by evaporationin a vacuum. The residue was purified by column chromatography on silicagel. 548 mg was obtained.

¹H-NMR (CDCl₃): δ=1.43-1.55 ppm m (2H); 1.62-1.83 m (6H); 2.32 t (J=7.5Hz, 2H); 3.68 s (3H); 3.90 t (J=7.5 Hz, 2H); 4.58 s (2H); 6.69 d (J=2Hz, 1H); 6.90 dd (J=8.2 Hz, 1H); 7.20-7.59 m (10H); 7.69 d (J=8 Hz, 1H).

EXAMPLE 386-[[1-Phenyl-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester

300 mg of6-[(2-benzylmercapto-1-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acidmethyl ester was dissolved in 6 ml of dichloromethane, mixed with 468 mgof m-chloroperbenzoic acid (about 60%), and the mixture was stirred for48 hours at 20° C. It was mixed with sodium disulfite solution,extracted twice with dichloromethane, the combined organic phases werewashed with saturated sodium bicarbonate solution, water and saturatedsodium chloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue was purified by columnchromatography on silica gel. 179 mg was obtained.

¹H-NMR (CDCl₃): δ=1.42-1.55 ppm m (2H); 1.58-1.84 m (4H); 2.33 t (J=7.5Hz, 2H); 3.66 s (3H); 3.85 t (J=7.5 Hz, 2H); 4.75 s (2H); 6.38 d (J=2Hz, 1H); 6.96 dd (J=8.2 Hz, 2H); 7.04 dd (J=8.2 Hz, 1H); 7.20-7.50 m(8H); 7.82 d (J=8 Hz, 1H).

EXAMPLE 396-[(2-Benzylmercapto-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid

235 mg of6-[(2-benzylmercapto-1-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acidmethyl ester was reacted with lithium hydroxide according to generaloperating instructions 3. 179 mg was obtained.

MS (EI): 446 (molecular ion peak).

EXAMPLE 406-[[1-Phenyl-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid

175 mg of6-[[1-phenyl-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was reacted with lithium hydroxide according togeneral operating instructions 3. 143 mg was obtained.

¹H-NMR (CDCl₃): δ=1.42-1.88 m (6H); 2.38 t (J=7.5 Hz, 2H); 3.85 t (J=7.5Hz, 2H); 4.75 s (2H); 6.38 d (J=2 Hz, 1H); 6.97 dd (J=8.2 Hz, 2H); 7.06dd (J=8.2 Hz, 1H); 7.18-7.50 m (8H); 7.83 d (J=8 Hz, 1H).

EXAMPLE 416-[[1-(4-Methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid

128 mg of6-[[1-(4-methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]-hexanoicacid methyl ester was reacted with lithium hydroxide according togeneral operating instructions 3. 98 mg was obtained.

MS (EI): 412 (molecular ion peak).

EXAMPLE 426-[[1-(4-Methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoicacid

147 mg of6-[[1-(4-methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]-hexanoicacid methyl ester was reacted with lithium hydroxide according togeneral operating instructions 3. 71 mg was obtained.

MS (EI): 444 (molecular ion peak).

EXAMPLE 436-[[2-Benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid

130 mg of6-[[2-benzylmercapto-1-(4-methylphenyl)-1H-benzimdiazol-6-yl]oxy]-hexanoicacid methyl ester was reacted with lithium hydroxide according togeneral operating instructions 3. 120 mg was obtained.

MS (EI): 460 (molecular ion peak).

EXAMPLE 446-[[1-(4-Methylphenyl-2-(phenylmethanesulfonyl)-1H-benzimdiazol-6-yl]-oxy]hexanoicacid

293 mg of6-[[1-(4-methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester was reacted with lithium hydroxide according togeneral operating instructions 3. 114 mg was obtained.

MS (EI): 492 (molecular ion peak).

EXAMPLE 45 Inhibition of Microglia Activation

For in vitro production of Aβ-activated microglia, primary rat microgliawith synthetic Aβ-peptide are incubated:

For simulation of Aβ deposits, synthetic Aβ peptide is dried on 96-holetissue culture plates. A peptide stock solution is diluted by 2 mg/ml ofH₂O 1:50 in H₂O. To coat the 96-hole plates, 30 μl of this dilutepeptide solution/hole is used, and it is dried overnight at roomtemperature.

Primary rat microglia are harvested by mixed glia cultures, which wereobtained from P3 rat brains. In the production of mixed glia cultures,the brains are taken from 3-day-old rats, and meninges are removed. Theisolation of cells is achieved by trypsinization (0.25% trypsinsolution, 15 minutes, 37° C.)). After undigested tissue fragments areseparated with the aid of a 40 μm nylon mesh, the isolated cells arecentrifuged off (800 rpm/10 minutes). The cell pellet is resuspended inthe culture medium and moved into 100 ml tissue culture flasks (1brain/tissue culture flask). The cultivation of the cells is carried outover a period of 5 to 7 days in Dulbeccos Modified Eagle Medium (DMEM,with glutamine), supplemented with penicillin (50 U/ml), streptomycin(40 μg/ml) and 10% (v/v) fetal calf serum (FCS) at 37° C. and 5% CO₂.During this incubation, an adhesive cellular film is formed, whichmainly consists of astrocytes. Microglia proliferate as non-adhesive orweakly adhesive cells on the latter and are harvested via shakingincubation (420 rpm, 1 hour).

To activate the microglia by Aβ-peptide, 2.5×10⁴ microglia/hole aregrown on the Aβ-coated tissue culture plates and incubated over a periodof 7 days in DMEM (with glutamine), supplemented with penicillin (50U/ml), streptomycin (40 μg/ml) and 10% (v/v) fetal calf serum (FCS) at37° C. and 5% CO₂. On day 5, a compound according to the invention isadded at various concentrations (0.1, 0.3, 1.3 and 10 μM).

To quantify the microglia reactivity, the metabolic activity is measuredon cultivation day 7 via the reduction of MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(sulfophenyl)-2H-tetrazolium),Owen's reagent, Baltrop, J. A. et al. Bioorg. & Med. Chem. Lett., 1,6111 (1991)). The percentage of inhibition relates to a control that istreated only with DMSO. The compounds according to the invention inhibitthe microglia activation. The compound of Example 9(6-[[1-(4-methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester shows an inhibition of IC₅₀=0.46 μM and the compoundof Example 156-[[2-(morpholin-4-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester shows an inhibition of IC₅₀=0.87 μM.

1. Benzimidazole derivatives with general formula I

in which R¹ stands for an aryl group, whereby the aryl group with up tothree radicals can be substituted independently of one another, selectedfrom the group consisting of: F, Cl, Br, C(NH)NH₂, C(NH)NHR⁴,C(NH)NR⁴R^(4′), C(NR⁴)NH₂, C(NR⁴)NHR^(4′), C(NR⁴)NR⁴R^(4′), X—OH, X—OR⁴,X—OCOR⁴, X—OCONHR⁴, X—COR⁴, X—C(NOH)R⁴, X—CN, X—COOH, X—COOR⁴, X—CONH₂,X—CONR⁴R^(4′), X—CONHR⁴, X—CONHOH, X—SR⁴, X—SOR⁴, X—SO₂R⁴, SO₂NH₂,SO₂NHR⁴, SO₂NR⁴R^(4′), NO₂, X—NH₂, X—NHR⁴, X—NR⁴R^(4′), X—NHSO₂R⁴,X—NR⁴SO₂R^(4′), X—NHCOR⁴, X—NHCOOR⁴, X—NHCONHR⁴ and R⁴, whereby X is abond, CH₂, (CH₂)₂ or CH(CH₃), and whereby also R⁴ and R^(4′),independently of one another, have the meanings that are furtherindicated below, and whereby two substituents at R¹ in each ease can belinked to one another in such a way that they Jointly form amethanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl orbutane-1,4-diyl group, if the substituents at R¹ are in ortha-positionto one another, Z stands for a grouping that is selected from the groupconsisting of S, SO and SO₂, R² is a radical that is selected from thegroup consisting of: (C₀₋₃-alkanediyl-C₃₋₇-cycloakyl), and(C₀₋₃-alkanediyl-aryl), whereby the aryl group can be substituted withup to two radicals, selected from the group consisting of F, Cl, Br,CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂, N(CH₃)₂, CF₃, C₂F₅ and SO₂NH₂ and/orcan carry an anellated methanediylbisoxy group and/orethane-1,2-diylbisoxy group, R³ stands for one or two substituents thatcan be selected independently of one another, selected from the groupconsisting of: F, Cl, Br, OH, OR⁴, OCOR⁴, OCONHR⁴, COR⁴, CN, COOH,COOR⁴, CONH₂, CONHR⁴, CONR⁴R^(4′), CONHOH, CONHOR⁴, SR⁴, SOR⁴, SO₂R⁴,SO₂NH₂, SO₂NHR⁴, SO₂NR⁴R^(4′), NO₂, NH₂, NHR⁴, NR⁴R^(4′), NHSO₂R⁴,NR⁴SO₂R^(4′), NHSO₂R⁶, NR⁴SO₂R⁶, NHCOR⁴, NHCOOR⁴, NHCONHR⁴ and R⁴,whereby radicals R⁴, R^(4′) and R⁶ are selected independently of oneanother and have the meanings that are further indicated below, A standsfor a group that is selected from the group consisting ofC₁₋₁₀-alkanediyl, C₂₋₁₀-alkenediyl, and C₂₋₁₀-alkinediyl, whereby in thealiphatic chains of the C₁₋₁₀-alkanediyl, C₂₋₁₀-alkenediyl, andC₂₋₁₀-alkinediyl groups, a C atom can also be exchanged for O, NH,N—C₁₋₃-alkyl or N—C₁₋₃-alkanoyl and whereby at least one of the alkylgroups can be substituted with a radical that is selected from the groupconsisting of ═O, OH, O—C₁₋₃-alkyl, NH₂, NH—C₁₋₃-alkyl,NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂ and N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl), Bstands for a radical that is selected from the group consisting of COOH,COOR⁵, CONH₂, CONHNH₂, CONHR⁵, CONR⁵R^(5′), CONHOH, CONHOR⁵ andtetrazolyl, whereby B is bonded to a C atom of group A, whereby radicalsR⁵ and R^(5′) are selected independently of one another and have themeanings that are further indicated below, Y stands for a group that isselected fium the group consisting of O, NH, NR⁴, NCOR⁴, NSO₂R⁴ andNSO₂R⁶, whereby radicals R⁴ and R⁶ have the meanings that are furtherindicated below, R⁴ and R⁴′ in each case stand for a radical that isselected from the group consisting of CF₃, C₂F₅, C₁₋₄-alkyl,C₂₋₄-alkenyl, C₂₋₃-alkinyl and (C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl),whereby a ring member in the cycloalkyl ring can be ring-N or ring-O ifthe cycloalkyl ring is five-membered, or one or two ring members in thecycloalkyl ring can be ring-N and/or ring-O atoms in each case if thecycloalkyl ring is six- or seven-membered, whereby the ring-N atoms canbe substituted with C₁₋₃-alkyl or C₁₋₃-alkanoyl, R⁵ and R^(5′) in eachcane stand for a radical that is selected from the group consisting ofC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl, whereby in at least one ofradicals R⁵ and R^(5′), a C atom can be exchanged for O, S, SO, SO₂, NH,N—C₁₋₃-alkyl or N—C₁₋₃-alkanoyl and (C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl),whereby a ring member in the cycloalkyl ring can be ring-N or ring-O ifthe cycloalkyl ring is five-membered, or one or two ring members in thecycloalkyl ring in each case can be one or two ring-N and/or ring-Oatoms if the cycloalkyl ring is six- or seven-membered, whereby thering-N atoms can be substituted with at least one radical that isselected from the group consisting of C₁₋₃-alkyl radicals andC₁₋₃-alkanoyl radicals, also (C₀₋₃-alkanediyl-aryl) and (C₀₋₃-alkanediylheteroaryl), whereby the heteroaryl group can be five- or six-memberedand can contain one or two heteroatoms, selected from the groupconsisting of N, S and O, whereby at least one of the alkyl andcycloalkyl radicals of R⁵ and R^(5′) also can be substituted with up totwo radicals, selected from the group consisting of CF₃, C₂F₅, OH,O—C₁₋₃-alkyl, NH₂, NH—C₁₋₃-alkyl, NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂,N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl), COOH, CONH₂ and COO—C₁₋₃-alkyl, and atleast one of the aryl and heteroaryl groups of R⁵ and R^(5′) can besubstituted with up to two radicals, selected from the group consistingof F, Cl, Br, CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂, N(CH₃)₂, CF₃, C₂F₅ andSO₂NH₂ and/or at least one of the alkyl, cycloalkyl, aryl and/orheteroaryl radicals of R⁵ and R^(5′) can carry an anellatedmethanediylbisoxy group or ethane-1,2-diylbisoxy group, or whereby R⁵and R^(5′) together with the amide-N-atom of B can form a five- toseven-membered, saturated or unsaturated heterocyclic ring, which cancontain another N or O or S atom, and which can tic substituted withC₁₋₄-alkyl, (C₀₋₂-alkanediyl-C₁₋₄-alkoxy), C₁₋₄-alkoxycarbonyl,aminocarbonyl or aryl, R⁶ stands for a radical that is selected from thegroup consisting of (C₀₋₃-alkanediyl-aryl) and(C₀₋₃-alkanediyl-heteroaryl), whereby the heteroaryl group is five- orsix-membered and contains one or two heteroatoms, selected from thegroup consisting of N, S and O, and whereby at least one of the aryl andheteroaryl groups can be substituted with up to two radicals in eachcase, selected from the group consisting of F, Cl, Br, CH₃, C₂H₅, OH,OCH₃, OC₂H₅, NO₂, N(CH₃)₂, CF₃, C₂F₅, and SO₂NH₂ or at least one of thearyl or heteroaryl groups can also carry an anellated methanediylbisoxygroup or ethane-1,2-diylbisoxy group.
 2. Benzimidazole derivativesaccording to claim 1, characterized in that R¹ stands fbr phenyl and canbe substituted with up to two radicals, independently of one another,selected from the group consisting of F, Cl, Br, C(NH)NH₂, C(NH)NHR⁴,C(NH)NR⁴R^(4′), C(NR⁴)NH₂, C(NR⁴)NHR^(4′), C(NR⁴)NR⁴R^(4′), H, OR⁴,OCOR⁴, OCONHR⁴, COR⁴, C(NOH)R⁴, CN, COOH, COOR⁴, CONH₂, CONR⁴R^(4′),CONNR⁴, CONHOH, SR⁴, SOR⁴, SO₂R⁴, SO₂NH₂, SO₂NHR⁴, SO₂NR⁴R^(4′), NO₂,NH₂, NHR⁴, NR⁴R^(4′), NHCONHR⁴ and R⁴.
 3. Benzimidazole derivativesaccording to claim 1, wherein R³ is a radical that is selected from thegroup consisting of hydrogen, F, Cl, Br, CH₃, C₂H₅, CF₃, C₂F₅, OH, OR⁴,NHSO₂R⁶ and NHCOR₄.
 4. Benzimidazole derivatives according to claim 1,wherein B stands for a radical that is selected from the groupconsisting of COOH, COOR⁵, CONH₂, CONHR⁵ and CONR⁵R^(5′). 5.Benzimidazole derivatives according to claim 1, wherein Y stands for O.6. Benzimidazole derivatives according to claim 1, wherein R⁶ stands fora phenyl or heteroaryl group, whereby the heteroaryl group is five, orsix-membered and contains one or two heteroatoms, selected from thegroup consisting of N, S and O.
 7. Benzimidazole derivatives of generalformula I according to claim 1, in which: R¹ means a phenyl group, whichcan be substituted with up to two radicals, independently of oneanother, selected from the group consisting of: F, Cl, Br, C(NH)NH₂,C(NH)NHR⁴, C(NH)NR⁴R^(4′), C(NR⁴)NH₂, C(NR⁴)NHR^(4′), C(NR⁴)NR⁴R^(4′),OH, OR⁴, OCOR⁴, OCONHR⁴, COR⁴, C(NOH)R⁴, CN, COOH, COOR⁴, CONH₂,CONR⁴R^(4′), CONHR⁴, CONHOH, SR⁴, SOR⁴, SO₂R⁴, SO₂NH₂, SO₂NHR⁴,SO₂NR⁴R^(4′), NO₂, NH₂, NHR⁴, NR⁴R^(4′), NHCONHR⁴ and R⁴, wherebyradicals R⁴ and R^(4′) according to meanings that are indicated beloware selected independently of one another and whereby two substituentsat R¹ are linked to one another in such a way that they jointly form amethanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl orbutane-1,4-diyl group, if they are in ortho-position to one another, Zmeans S, SO or SO₂, R² is (C₀₋₃-alkanediyl-aryl), whereby the aryl groupcan be substituted with up to two radicals, selected from the groupconsisting of F, Cl, Br, CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂, CF₃, C₂F₅ andSO₂NH₂, R³ means hydrogen, A means straight-chain or branched alkanediylwith up to 8 C atoms, B means a radical that is selected from the groupconsisting of COOH, COOR⁵, CONH₂, CONHR⁵ and CONR⁵R^(5′), in each casebonded to a C atom of group A, whereby radicals R⁵ and R^(5′), accordingto the meanings that are further indicated below, are selectedindependently of one another, Y means O, in which in the above radicals,radicals R⁴, R^(4′), R⁵, and R^(5′), have the following meanings: R⁴ andR^(4′), independently of one another, in each case mean a radical thatis selected from the group consisting of CF₃, C₂F₅, C₁₋₄-alkyl,C₂₋₄-alkenyl, C₂₋₃-alkinyl and (C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl),whereby alkyl radicals optionally can be substituted with a radical thatis selected from the group consisting of OH, OCH₃ and SCH₃, R⁵ andR^(5′), independently of one another, in each case mean a radical thatis selected from the group consisting of C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkinyl, (C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl), (C₀₋₃-alkanediyl-aryl)and (C₀₋₃-alkanediyl-heteroaryl), whereby the heteroaryl group is five-or six-membered and contains one or two heteroatoms, selected from thegroup consisting of N, S and O, whereby all previously mentioned alkyland cycloalkyl radicals can be substituted with a radical that isselected from the group consisting of CF₃, C₂F₅, OH, O—C₁₋₃-alkyl, NH₂,NH—C₁₋₃-alkyl, NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂,N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl), COOH, CONH₂ and COO—C₁₋₃-alkyl, and allpreviously mentioned phenyl and heteroaryl groups can be substitutedwith up to two radicals, selected from the group consisting of F, Cl,Br, CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂, N(CH₃)₂, CF₃, C₂F₅ and SO₂NH₂,and/or also can carry an anellated methanediylbisoxy group orethane-1,2-diylbisoxy group, or R⁵ and R^(5′) together with the amide-Natom of B form a five- to seven-membered, saturated or unsaturatedheterocyclic ring, which can contain another N or O or S atom and whichcan be substituted with C₁₋₄-alkyl, (C₀₋₂-alkanediyl-C₁₋₄-alkoxy),C₁₋₄-alkoxycarbonyl, aminocarbonyl or phenyl.
 8. Benzimidazolederivatives according to claim 7, wherein R⁵ and R^(5′) in each casestand for a radical that is selected from the group consisting ofC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl,(C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl), (C₀₋₃-alkanediyl-aryl) and(C₀₋₃-alkanediyl-heteroaryl), whereby aryl stands for phenyl and thealkyl and cycloalkyl radicals are substituted with a radical that isselected from the group consisting of CF₃, C₂F₅, OH, O—C₁₋₃-alkyl, NH₂,NH—C₁₋₃-alkyl, NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂,(—N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl), COOH, CONH₂, and COO—C₁₋₃-alkyl. 9.Benzimidazole derivatives according to claim 7, wherein aryl in R¹stands for phenyl (C₆H₅—) or p-methyl-phenyl (p-CH₃—C₆H₄—). 10.Benzimidazole derivatives according to claim 7, wherein R² stands forphenyl, methylphenylene, or benzyl.
 11. Benzimidazole derivatives ofgeneral formula I, namely6-[[2-Benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester,6-[[1-(4-Methylphenyl)-2-(phenylmethanesulfinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester,6-[[1-(4-Methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester,N-(3-Methoxypropyl)-6-[[1-(4-methylphenyl)-2-benzylmercapto-1-H-benzimidazol-6-yl]oxy]hexanamide,N-(3-Methoxypropyl)-6-[[1-(4-methylphenyl)-2-(-phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanamide,6-[[1-(4-Methylphenyl)-2-phenylmercapto-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester,6-[[1-(4-Methylphenyl)-2-(phenylsulfinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester,6-[[1-(4-Methylphenyl)-2-(phenylsulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester,6-[(2-Benzylmercapto-1-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acidmethyl ester,6-[[1-Phenyl-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester,6-[(2-Benzylmercapto-1-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid,6-[[1-Phenyl-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid,6-[[2-Benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid, or6-[[1-(4-Methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid.
 12. Pharmaceutical preparations that contain at least onebenzimidazole derivative with general formula I according to one ofclaims 1 to 11 as well as at least one pharmaceutically compatiblevehicle.
 13. A method of treating inflammatory or allergic diseasescomprising administering an effective amount of a benzimidazolederivative with general formula I according to one of claims 1 to 11 toa patient in need thereof.
 14. The method of claim 13 wherein thedisease treated is stroke.